Compositions for treatment of attention deficit hyperactivity disorder

ABSTRACT

Therapeutic compositions deliver a therapeutic amount of methylphenidate in a delayed and extended release formulation. The dosage form exhibits a lag time prior to release of from 6 to 8 hours or longer, followed by a sustained release period.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/227,932 filed Dec. 20, 2018, which is a continuation of U.S.application Ser. No. 15/359,202, filed Nov. 22, 2016, now U.S. Pat. No.10,182,995. which is a continuation of co-pending U.S. application Ser.No. 15/069,734, filed Mar. 14, 2016, now U.S. Pat. No. 9,498,447, whichis a continuation of U.S. aplication Ser. No. 14/704,836, filed May 5,2015, now U.S. Pat. No. 9,283,214, which is a continuation-in-part ofU.S. application Ser. No. 14/589,839, filed Jan. 5, 2015, now U.S. Pat.No. 9,023,389, which is a continuation of U.S. application Ser. No.14/230,053, filed Mar. 31, 2014, now U.S. Pat. No. 8,927,010, which is acontinuation-in-part of U.S. application Ser. No. 13/429,292, filed Mar.23, 2012, now U.S. Pat. No. 9,028,868, which claims benefit of priorityto U.S. Provisional Application Nos. 61/466,684, filed Mar. 23, 2011,61/561,763, filed Nov. 18, 2011 and 61/591,129, filed Jan. 26, 2012, allof which are incorporated herein by reference in their entirety.

BACKGROUND

Attention deficit hyperactivity disorder (ADHD) is a developmentaldisorder characterized by symptoms such as impulsiveness, hyperactivityand/or inattentiveness. Hyperactivity is common among children with ADHDbut tends to disappear during adulthood. However, over half of childrenwith ADHD continue to have some symptoms of inattention throughout theirlives.

Stimulant medications are widely used as a pharmacological treatment forADHD. Stimulants, in the short term, have been found to be safe in theappropriately selected patient and appear well tolerated over five yearsof treatment. Active pharmaceutical agents now approved in the USA foruse in treatment of ADHD are primarily effectors of the dopamine ornorepinephrine neural pathways. Approved agents include salts andisomers of amphetamine and methylphenidate, the dextroamphetamineprodrug, lisdexamfetamine dimesylate, and atomoxetine.

One of the challenges of treating ADHD and other CNS stimulantresponsive conditions is delivering and maintaining an effectiveconcentration in patients throughout the day and in particular, in themorning hours when cognitive abilities and concentration are needed forschool or work and in the late afternoon or evening when students oftendo homework. Early formulations relied on a twice daily administrationof an immediate release formulation, causing problems with compliance.Various long-acting formulations were developed and are now availablethat have been shown in clinical trials to be effective for 8-14 hours(Brams et al., Current Medical Research and Opinion, vol. 26 no. 8, pgs1809-1825, August 2010).

SUMMARY

The compositions and methods of the present disclosure provide novelformulations and methods for treating diseases or conditions that areresponsive to CNS stimulants. Such conditions include but are notlimited to ADD, ADHD, narcolepsy, excessive daytime sleepiness, majordepressive disorder, bipolar depression, negative symptoms inschizophrenia, chronic fatigue, fatigue associated with chemotherapy orbinge eating disorder. The compositions and methods are effective fortreating the adult, pediatric and adolescent populations that are inneed of such treatment.

The disclosed compositions and methods provide a convenient method ofadministration in that a single dose can be taken typically in theevening prior to going to bed, or at whatever time of day one retiresfor an extended period of sleep and the release of the drug is delayedfor 4 to 12 hours in some examples and then released in a controlled orsustained manner. It is an aspect of the disclosure that the lag timecan be controlled through design of the formulation and that the lag canthus be 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours or intermediate timeswithin the range. It is also understood that the administration time isnot necessarily tied to a patient's sleep time or sleep cycle, but thatadministration can be from 4-12 hours prior to the time a patient needsa therapeutic dose whether he or she sleeps during the lag or not.

In certain embodiments, the compositions are water-soluble capsules thatcontain coated such as beads or minitablets. These particles are coatedwith an outer, delayed release coating and an inner, sustained releasecoating over a drug containing core. The delayed release allows thesubject to sleep, and as the outer layer of the composition dissolvesand the sustained release layer begins to lose some of its integrity,the drug starts to slowly release. This results in a low, buttherapeutic level of drug in the plasma of the patient when that patientwould normally wake up and prepare for the day. Subsequent to this slowrelease, the drug release rate increases over a period of about eight toten hours or more, to continue to provide a therapeutic amount duringthe typically active part of the day. The compositions and methodsdisclosed herein thus provide a single dose that is conveniently takenprior to sleeping and that provides a therapeutic effect from the time asubject normally awakes and through the productive portion of the day.

Although the present compositions are described as effective as aonce-a-day dosage, it is understood that additional doses can beadministered as needed at the direction of a physician. The descriptionherein is primarily directed to treatment of persons with a typicalschedule of going to sleep from around 9 P.M. to about midnight, forexample, and sleeping for 6-9 hours. It is understood, however, that theuse and efficacy of the compositions and methods is not limited to sucha schedule, but can be adopted for use with different daily schedules,such as night workers, or people with longer, shorter or more variablesleep patterns.

In certain embodiments, the compositions disclosed herein include, butare not limited to tablets, minitablets or beads contained in awater-soluble capsule. The minitablets or beads can include a drugcontaining core or a drug coated inert bead core in which the drug coreor drug layer can also contain an optional disintegrant, osmagent orpore-forming agent. In certain embodiments the disintegrant can be asuperdisintegrant. In certain embodiments the drug layer or core isenclosed by a sustained release layer that can include a water-insolubleand water permeable polymer layer that controls the rate of absorptionof water and release of the drug. The outer, delayed release layer iscoated on the sustained release layer. The delayed release layer maycontain a plasticizer or solubility can be pH dependent. The delayedrelease layer can thus be a pH dependent layer that is insoluble inaqueous solution at a pH below 5.5 and soluble at the higher pH normallyfound in the ileum or colon, or it can be a pH independent layer. Incertain embodiments, an outer, pH dependent layer dissolves in thehigher pH of the ileum or colon. As the sustained release layer thenloses integrity the sustained release layer ruptures and releases theremaining drug in the core.

The active ingredients include CNS stimulants that are effective totreat ADD and ADHD or other conditions associated with dopamine ornorepinephrine neural pathways. The active ingredients include, but arenot limited to the active isomers of amphetamines and amphetamine salts,or mixed amphetamine salts, including salts of dextroamphetamine, andmethylphenidate and its active salts, all of which can be used asracemic mixtures or pure isomers such as d-threo methylphenidate. Thedisclosed compositions can also include one or more prodrug of CNSstimulants, including but not limited to amino acid conjugated activeingredients such as l-lysine-d-amphetamine, for example.

The compositions and methods of the present disclosure can be describedin certain embodiments, therefore, as solid, oral pharmaceuticalcompositions including a core comprising a therapeutic amount of a CNSstimulant, at least one pharmaceutically acceptable excipient andoptionally a disintegrant, osmagent, or a pore-forming agent; asustained release layer coating the core; and a delayed release layerenclosing the sustained release layer, wherein the combination of thesustained release and delayed release layers provide a 3-8, 10 or even12-13 hour delay during which no more than 10% of the CNS stimulant isreleased when the composition is placed in a simulated gastricenvironment. The term simulated gastric environment is intended to beused herein to convey its ordinary meaning as understood in the art, andis understood in a broad sense to mean conditions that mimic oraladministration, for example, an aqueous environment of low pH, 1-5 forexample, followed after a period of up to about 2 hours with immersionin a higher pH aqueous environment, such as pH 6.8, for example, or a 3stage environment in which the low pH is followed by an intermediate pHof about 6 wherein the environments are maintained at about 37.0° C.Alternatively, for certain embodiments a simulated gastric environmentis described as the USP Apparatus I (Baskets) with agitation in whichthe composition is placed in 700 ml aqueous solution of 0.1N HCl pH 1.1,for up to 2 hours followed by 2-6 hours in sodium phosphate buffer at pH6.0; followed by 6-20 hours in sodium phosphate buffer, pH 7.2, addingNaOH to adjust pH to 7.2.

Any of the solid oral pharmaceutical compositions disclosed herein canbe in the form of coated beads, or they can be compressed into tablet orminitablet form. The beads or minitablets can then be apportioned insingle dose amounts into water-soluble gelatin capsules, or into aliquid or gel suspension for administration.

An aspect of the compositions and methods of the present disclosure canalso be described as solid, oral pharmaceutical compositions including acore comprising a therapeutic amount of a CNS stimulant and at least onepharmaceutically acceptable excipient wherein the core is substantiallyfree of a disintegrant, osmagent, or a pore-forming agent; a sustainedrelease layer coating the core; and a delayed release layer enclosingthe sustained release layer, wherein the combination of the sustainedrelease and delayed release layers provide a 3, 4, 5, 6, 7, 8, 9, 10, 11or even a 12 hour delay during which no more than 10% of the CNSstimulant is released when the composition is placed in a simulatedgastric environment.

A solid, oral pharmaceutical composition of the disclosure can bedescribed as a formulation in which the in vitro dissolution rate of thedosage form when measured by the USP Apparatus I (Baskets) withagitation in which the composition is placed in 700 ml aqueous solutionof 0.1N HCl pH 1.1, for up to 2 hours followed by 2-6 hours in sodiumphosphate buffer at pH 6.0; followed by 6-20 hours in sodium phosphatebuffer, pH 7.2, adding NaOH to adjust pH to 7.2 at 37° C.±0.5° C. isbetween 0 and about 20% drug released after 8 hours, between about 2 andabout 30% released after 10 hours, between about 10% and about 65%released after 12 hours and between 45% and 95% released after 15 hours,and wherein the amount of active ingredient released per each hourincreases from the period between 20% released and 65% released. Thecompositions and methods of the present disclosure can also be describedas solid, oral pharmaceutical compositions in which the in vitrodissolution rate of the dosage form when measured by the USP Apparatus I(Baskets) with agitation in which the composition is placed in 700 mlaqueous solution of 0.1N HCl pH 1.1, for up to 2 hours followed by 2-6hours in sodium phosphate buffer at pH 6.0; followed by 6-20 hours insodium phosphate buffer, pH 7.2, adding NaOH to adjust pH to 7.2 at 37°C.±0.5° C. is between 0 and about 10% drug released after 6 hours,between about 15% and about 28% released after 10 hours, between about40% and about 60% released after 12 hours and between about 80% andabout 95% released after 15 hours, and wherein the amount of activeingredient released per each hour increases from the period between 20%released and 65% released, or as a solid, oral pharmaceuticalcomposition as described when measured by the USP Apparatus I (Baskets)with agitation in which the composition is placed 700 ml aqueoussolution of 0.1N HCl pH 1.1, for up to 2 hours followed by 2-6 hours insodium phosphate buffer at pH 6.0; followed by 6-20 hours in sodiumphosphate buffer, pH 7.2, adding NaOH to adjust pH to 7.2 at 37° C.±0.5°C., no more than about 10% of the agent is released within 6 hours andno more than about 50% of the agent is released within 12 hours, andwherein, when the composition is administered to a human, a plot ofplasma concentration versus time after administration exhibits a singlemaximum between 12 and 20 hours after administration.

The solid oral pharmaceutical compositions of the present disclosure canalso include a plurality of core pellets that in certain embodiments aresubstantially spherical beads. By substantially spherical beads is meanta population of beads in which the measured mean area ratio andcircularity, are within 80% of a sphere. The core can consistessentially of a CNS stimulant and one or more excipients, or the corecan consist essentially of the stimulant and one or more excipientscoated on an inert non-pareil bead. These cores are then coated with twoor more release control layers to produce a population of particles fordrug delivery. It is an aspect of the compositions and methods of thepresent disclosure, however, that it is advantageous to provide a smoothspherical core to the extent possible in order to obtain a moreconsistent coating and a reproducible release profile of the activeingredient from the populations of particles.

The solid oral pharmaceutical compositions of the present disclosurealso include a CNS stimulant which can be generally defined as achemical entity that affects the dopamine or norepinephrine neuralpathways. Preferred pharmaceutically active ingredients include, but arenot limited to amphetamine, dextroamphetamine, the active isomers ofamphetamines and amphetamine salts including salts of dextroamphetamine,methylphenidate and its active salts, or combinations thereof, all ofwhich can be used as racemic mixtures or pure isomers such as d-threomethylphenidate, or a prodrug or pharmaceutical salt, or mixedpharmaceutical salts of any thereof alone or in combination. Thedisclosed compositions can also include a prodrug, including but notlimited to amino acid conjugated active ingredients such asl-lysine-d-amphetamine. Suitable excipients in the core of thepharmaceutical composition can include polyvinyl pyrollidone,hydroxypropylmethyl cellulose, lactose, sucrose, microcrystallinecellulose or combinations of any thereof.

It is an aspect of the disclosed compositions that the delayed releaselayer can include a pH dependent polymer or copolymer that is insolublein aqueous medium at pH lower than 5.5. Such a delayed release layer caninclude, but is not limited to cellulose acetate phthalate, celluloseacetate trimaletate, hydroxyl propyl methylcellulose phthalate,polyvinyl acetate phthalate, acrylic polymers, polyvinylacetaldiethylamino acetate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate trimellitate, shellac, methacrylic acidcopolymers, Eudragit L30D, Eudragit L100, Eudragit FS30D, Eudragit S100or combinations of any thereof. The delayed release layer can alsoinclude a plasticizer, or in certain embodiments the delayed releaselayer can include methacrylic acid copolymer Type B, mono- anddiglycerides, dibutyl sebacate and polysorbate 80.

In certain embodiments of the disclosed solid oral pharmaceuticalcompositions, the sustained release layer includes a water-insoluble andwater-permeable polymer and can further include a water-soluble polymer.In certain embodiments, the sustained release layer includes, but is notlimited to a cellulose ether derivative, an acrylic resin, a copolymerof acrylic acid and methacrylic acid esters with quaternary ammoniumgroups, a copolymer of acrylic acid and methacrylic acid esters or acombination of any thereof, or it can include ethyl cellulose,hydroxypropyl cellulose, dibutyl sebacate and a stearate salt such asmagnesium stearate. It is understood that the carboxylic acid, steraratecan be associated with various cationic species including mono anddivalent metals to produce a nontoxic salt. Such salts can include butare not limited to sodium, potassium, magnesium, zinc, or calciumstearates.

In certain embodiments the core can include a disintegrant and caninclude corn starch, potato starch, a pre-gelatinized starch, a modifiedstarch, a sweetener, a clay, bentonite, microcrystalline cellulose,carboxymethylcellulose calcium, croscarmellose sodium, alginic acid,sodium alginate, cellulose polyacrilin potassium, an alginate, sodiumstarch glycolate, a gum, agar, guar, locust bean, karaya, pectin,tragacanth, crospovidone or low substituted hydroxypropyl cellulose. Thecompositions can also include a disintegrant, osmagent, or apore-forming agent, which can be a salt, an acid, a base, a chelatingagent, sodium chloride, lithium chloride, magnesium chloride, magnesiumsulfate, lithium sulfate, polyol, mannitol, sulfatol, xylitol, acarbohydrate, a carbonate, a bicarbonate, electrolyte, potassiumchloride, sodium sulfite, calcium bicarbonate, sodium sulfate, calciumsulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose,sucrose, alpha-d-lactose monohydrate, glucose, alpha-hydroxy acids,citric acid, ascorbic acid, or a combination of any thereof. It is afurther aspect of the disclosure that the disclosed formulations caninclude an abuse deterrent agent that can be a nasal irritant such as acapsaicinoid or sodium lauryl sulfate.

In certain embodiments the optional disintegrant, osmagent, orpore-forming agent constitutes from 0 to about 75% of the core byweight. The compositions can also include a swellable layer or a sealinglayer disposed between the core and the sustained release layer. Theswellable layer can include a superdisintegrant, an osmotic agent, or acombination thereof, and in certain embodiments includes a hydrophilicpolymer such as polyethylene oxide and a binder and can further includea drug containing layer between the swellable layer and the sustainedrelease layer and can include a seal between the swellable layer and thedrug containing layer.

In certain embodiments the compositions and methods of the presentdisclosure can be described as a method of treating a condition in asubject with a disorder or condition responsive to the administration ofa CNS stimulant, comprising orally administering the disclosed solid,oral pharmaceutical compositions. The method of treatment can includeadministering a single dosage form or two per day depending on the needof a particular patient. It is an aspect of the compositions and methodsof the present disclosure that the administration of the dosage form ona once-a-day basis provides a delayed release of from about 4 to about12 hours, followed by an increasing plasma concentration profile, whichfor a 24 hour period commencing with an administration of the dosageform results in a maximum plasma concentration (C_(max)) which occurs atleast 12 hours, at least 14 hours, or at least 15 hours afteradministration.

The compositions and methods of the present disclosure can also bedescribed in certain embodiments as solid, oral pharmaceuticalcompositions including a therapeutic amount of a CNS stimulant whereinthe composition, when orally administered to a human, provides a delayedrelease of from 4 to 12 hours, an ascending plasma concentration of CNSstimulant for a period of from 7 to 12 hours and a maximum plasmaconcentration (C_(max)) from 10 to 19 hours after administration. Incertain embodiments, the plasma concentration exhibits a single maximum.

The compositions and methods of the present disclosure can also bedescribed in certain embodiments as solid, oral pharmaceuticalcompositions comprising a core comprising a therapeutic amount of a CNSstimulant and at least one pharmaceutically acceptable excipient whereinthe core is substantially free of a disintegrant, osmagent, or apore-forming agent; a sustained release layer coating the core; and adelayed release layer enclosing the sustained release layer, whereinwhen the composition is placed in a simulated gastric environment, thecombination of the sustained release and delayed release layers provide:a mean 3 to 12 hour delay during which no more than 10% of the CNSstimulant is released and a mean ascending release of CNS agent from8-16 hours after being placed in the simulated gastric environment.

Conditions or disorders that can be treated include, but are not limitedto ADD, ADHD, excessive daytime sleepiness, major depressive disorder,bipolar depression, negative symptoms in schizophrenia, chronic fatigue,fatigue associated with chemotherapy or binge eating disorder. Attentiondeficit disorders are characterized by hyperactive, impulsive orinattentive symptoms that cause impairment in social, academic, oroccupational functioning, and are often present in two or more settings,school (or work) and at home, for example. For the Inattentive Type, atleast 6 of the following symptoms have persisted for at least 6 months:lack of attention to details/careless mistakes; lack of sustainedattention; poor listener; failure to follow through on tasks; poororganization; avoids tasks requiring sustained mental effort; losesthings; easily distracted; and forgetful. For the Hyperactive-ImpulsiveType, at least 6 of the following symptoms have persisted for at least 6months: fidgeting/squirming; leaving seat; inappropriaterunning/climbing; difficulty with quiet activities; “on the go”;excessive talking; blurting answers; can't wait turn, and intrusivebehavior. The combined type includes both inattentive andhyperactive-impulsive behaviors.

It is understood that the term “treatment” as used herein is not limitedto the cure or elimination of any condition or disorder nor is that termlimited to the achievement of certain milestones or improvement criteriain a particular subject, but includes the administration of an agent forthe purpose of achieving positive effects in terms of cognitive orbehavioral function, reduction of symptoms or side effects. All suchactivities are considered to be treatment whether or not any improvementis immediately observable or measurable.

It is well known, for example, that certain side effects may occur inconjunction with administration of CNS stimulants. It is also known thatthese side effects can be related to the blood concentrations ofstimulants in particular patients. These side effects can include, butare not limited to headache, nausea, dizziness, hot flush, decreasedappetite, insomnia, abdominal discomfort (stomach ache), dry mouth, fastheartbeat, nervousness, mood swings, irritability, weight loss, orcomplaints of just not feeling good, with the most significant oftenbeing sleep or appetite related complaints. It is contemplated thattreatment with the disclosed formulations will result in reducedincidence or severity of side effects relative to treatments in whichthe active agent is rapidly released in the stomach. As such, treatmentwould encompass not only reduction of symptoms of the condition ordisorder but also reduction in side effects.

The compositions and active agents of this disclosure are administeredin an “effective amount,” “effective dose,” or “therapeuticallyeffective amount or dose.” By an “effective” amount or a“therapeutically effective amount” or dose of a drug orpharmacologically active agent is meant a nontoxic but sufficient amountof the drug or agent to provide the desired effect. In the currentdisclosure, an “effective amount” is the amount of that composition oractive agent that is effective to improve, ameliorate or prevent one ormore symptoms of the condition being treated. The amount that is“effective” will vary from subject to subject, depending on the age,weight and general condition of the individual, or the particular activeagent. A therapeutic or effective dose or amount is determined by aphysician and is often based on empirical data obtained by administeringincreasing doses until the best balance of benefit vs. side effects isreached.

An effective dose in the compositions of the present disclosure,particular for treatment of ADHD include doses shown to be effective inthe treatment of those conditions by oral dosage, including but notlimited to 5, 9, 10, 15, 18, 20, 25, 27, 30, 35, 36, 45 or 54 mg once ortwice daily, or the bioequivalent of such doses of the same activeingredient in an immediate release formulation. As such, the effectivedose can be 60, 65, 70, 75, 80, 85, 90, 100 or up to 150 mg once ortwice a day. It is also understood that other dosage ranges may beeffective for conditions or symptoms other than ADHD and as such, thetherapeutically effective drug concentration in the disclosedcompositions can be from 0.1 to 1000 mg inclusive of any particularconcentration within that range.

As used herein, the term “pharmaceutically acceptable salt” refers tonon-toxic pharmaceutically acceptable salts as described (Ref.International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997(January), 86, 1, 1). Other salts well known to those in the art may,however, be useful in the preparation of compositions of the disclosureincluding, but not limited to, hydrochloric, hydrobromic, hydriodic,perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic,lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic,mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic,oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.Representative organic or inorganic bases include, but are not limitedto, basic or cationic salts such as benzathine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium,lithium, magnesium, potassium, sodium and zinc.

The compositions and methods of the present disclosure can also bedescribed in certain embodiments as solid, oral pharmaceuticalcompositions comprising a therapeutic amount of a CNS stimulant whereinthe composition, when orally administered to a human, provides a delayedrelease of from 3-8 hours, an ascending rate of release of CNS stimulantfor a period of from 7-12 hours and a maximum plasma concentration(C_(max)) from 10-16 hours after administration, and wherein a plot ofthe plasma concentration versus time after release can exhibit a singlemaximum, rather than two or more pulses of drug release. The solid oralpharmaceutical can be further defined as one in which no more than 10%of the CNS stimulant is released within 6 hours after administration.

In certain embodiments the compositions and methods of the presentdisclosure can be defined as solid, oral pharmaceutical compositionscomprising: a core comprising a therapeutic amount of a CNS stimulantand at least one pharmaceutically acceptable excipient, a sustainedrelease layer coating the core, and a delayed release layer enclosingthe sustained release layer, wherein the core is substantially free of adisintegrant, osmagent, or a pore-forming agent; wherein when thecomposition is administered to a human, the combination of the sustainedrelease and delayed release layers provide: a mean 3-8 hour delay duringwhich no more than 10% of the CNS stimulant is released; a meanascending plasma concentration of CNS agent from the onset of absorptionto a period of from 12-16 hours after administration and in which theplasma concentration exhibits a single maximum.

The present disclosure can be described therefore in certain embodimentsas a solid, oral pharmaceutical composition including a singlepopulation of beads, with beads including a core comprisingmethylphenidate or a pharmaceutical salt thereof and at least onepharmaceutically acceptable excipient, a sustained release layerenclosing the core; and a delayed release layer enclosing the sustainedrelease layer. The sustained release layer can be a layer that releasesthe drug in a sigmoidal release curve in which a slow initial releaseperiod is followed by a period of more rapid release. Such a releasepattern will also include an inflection point in which the rate ofrelease decreases somewhere in the intermediate period between start ofrelease and total release. This point can be most clearly determined bya “Hill Plot”, or a plot of the first derivative of the release profile.The inflexion point is defined as the point at which the Hill plottransitions from a positive slope to a negative slope.

The oral formulation can be administered to a human subject in a fastedstate resulting in a pharmacokinetic profile which includes a lag of atleast 7 hours during which the plasma concentration of methylphenidateis less than 5% of the maximum plasma concentration (C_(max)), a plasmaarea under the curve at 10 hours (AUC₀₋₁₀) after administration that isless than about 7% of AUC₀₋₄₈, and wherein the time to C_(max) (T_(max))is between 12 and 19 hours after administration. The describedadministration to a population of subjects also provides a significantimprovement in ADHD related behavior or cognitive ability over a periodof at least 12 continuous hours as measured by a validated rating scale.The meaning of a validated rating scale is described in more detailbelow.

In the practice of the disclosure, the improvement can be measured bythe ADHD-RS-IV scale, BSFQ, CGI, CGI-P, PREMB, Permanent Product Measureof Performance (PERMP) scores, or SKAMP rating scale, for example, or byany validated rating scale as defined herein or known to those of skillin the art. It is an aspect of the disclosure that the formulationprovides a significant improvement in Permanent Product Measure ofPerformance scores over a period of at least about 12 continuous hourswhen administered to a population of patients including adult,adolescent or child subjects. Administration of the disclosedcompositions also provides a significant improvement over placebo inPermanent Product Measure of Performance scores over a period from about11 through about 23 hours post-dose. For example, when the formulationis administered at about 8-10 PM, the formulation provides a significantimprovement in PERMP scores during a 10-12 hour period from about 7 AMto about 9 PM the following day, and can include at least a 50%improvement over placebo.

As described herein, the formulation can also provide a significantimprovement in SKAMP scores during a period of about 12 continuous hoursand the improvement can be during a period from about 11 through about23 hours post-dose. For example, when the formulation is administered atabout 8-10 PM, it provides a significant improvement in SKAMP scoresduring a 10-12 hour period from about 7 AM to about 9 PM the followingday.

The disclosed compositions also can provide a measureable improvement inearly morning performance and control of symptoms of ADHD as measured byBSFQ scores over placebo when the composition is administered at about8-10 PM. As described elsewhere herein, much of the disclosure iswritten in reference to treatment of attention deficit disorders, butthe compositions and methods as described herein are not limited to apreferred embodiment, but can be used in the treatment of attentiondeficit disorder, attention deficit hyperactivity disorder, excessivedaytime sleepiness, major depressive disorder, bipolar depression,negative symptoms in schizophrenia, chronic fatigue, fatigue associatedwith chemotherapy or binge eating disorder, for example, or for otherconditions that respond to a CNS stimulant.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinventions. The disclosure can be better understood by reference to oneor more of these drawings in combination with the detailed descriptionof specific embodiments presented herein.

FIG. 1A is a schematic representation of a bead pharmaceuticalcomposition with a drug containing core surrounded by a sustainedrelease layer and a delayed release layer. FIG. 1B a composition as in1A with an added swellable layer disposed between the sustained releaselayer and the drug containing core.

FIG. 2A is a schematic representation of a minitablet pharmaceuticalcomposition with a drug containing core surrounded by a sustainedrelease layer and a delayed release layer. FIG. 2B a composition as in2A with an added swellable layer disposed between the sustained releaselayer and the drug containing core.

FIG. 3 is a schematic representation of a bead pharmaceuticalcomposition that includes a core surrounded by 4 layers, an inert innercore, a swelling polymer, a drug layer, a sustained release layer and anenteric layer.

FIG. 4 is a graph of dissolution profiles of DOE 1-8.

FIG. 5 is a graph of dissolution profiles of DOE 9, 10, 11, 3, 4.

FIG. 6 is a graph of stability dissolution profile of DOE 4.

FIG. 7 is a graph of stability dissolution profile of DOE 3.

FIG. 8 is a graph of enteric coating on DOE 3 (3-Stage) dissolutionprofile.

FIG. 9 is a graph of dissolution of DOE 3 coatings.

FIG. 10 is a graph of dissolution profile of Lot 2009-138-45 (30% WeightGain).

FIG. 11 is a graph of two-week stability dissolution profile.

FIG. 12 is a graph of dissolution profile of DOE 3 (Lot 2009-138-45)cured at 50° C.

FIG. 13 is a graph of dissolution profile DOE 3 (Lot 2009-138-45) curedat 55° C.

FIG. 14 is a graph of dissolution profile of DOE 3 (Lot 2009-138-45)cured at 55° C. on stability.

FIG. 15 is a graph of dissolution profile of DOE 3 (Lot 2009-138-45) 8month stability.

FIG. 16 is a graph of the dissolution profiles of the formulationsdescribed in Examples 14-18.

FIG. 17 is a graph of the plasma concentration of healthy volunteersafter ingesting the formulations of Examples 14-18.

FIG. 18 is a comparison of the data of FIG. 17 with commerciallyavailable formulations.

FIG. 19 is a comparison of mean plasma concentration of commerciallyavailable Ritalin® with the methylphenidate test formulas as describedin Example 28.

FIG. 20 is a comparison of mean plasma concentration of commerciallyavailable Concerta® with the methylphenidate test formulas as describedin Example 28.

FIG. 21 is a graph showing the gender effect in the comparison withConcerta® from Example 28.

FIG. 22 is a comparison of mean plasma concentration time values for themodified release (MR) formulations MPH004 and MPH005 and the referenceRitalin® described in Example 28.

FIG. 23 is a comparison of mean plasma concentration time values for a100 mg dose of HLD200 taken in a fed state, a fasted state and sprinkledon apple sauce as described in Example 29.

FIG. 24 is mean plasma concentration time values for adolescent andpediatric subjects after administration of MR methylphenidate asdescribed in Example 30.

FIG. 25 is a graph of the dissolution results for 2 formulations, (i) afast release formulation with a 20% weight gain SR coating and a 15%weight gain EC coating, and (ii) a slow release formulation with a 20%weight gain SR coating and a 30% weight gain EC coating.

FIG. 26 is a graph of the primary endpoint SKAMP analysis from theclinical trial described in Example 32.

FIG. 27 is a graph of the SKAMP combined score analysis from theclinical trial described in Example 32.

FIG. 28 is a graph of the BSFQ scores from the clinical trial describedin Example 32.

FIG. 29 is a graph of the PERMP combined scores from the clinical trialdescribed in Example 32.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides therapeutic compositions and methods fortreatment of attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD) or other conditions or disordersresponsive to CNS stimulants by providing dosage forms that deliver atherapeutic amount of active drug in a delayed and controlled releasepattern in order to maintain a therapeutic amount of drug through theactive portion of the day. For pediatric patients including adolescentsand also for adults, a therapeutic amount is desirable upon arising andthroughout the morning, as well as through the afternoon hours in whichwork or homework needs to be done.

The disclosed formulations can provide a therapeutic amount of drugduring extended periods of the day with a single administration. Thedosage forms provide a delayed release such that the dosage form can beadministered conveniently prior to the patient's sleeping. A smallpercentage of the drug can be released over the first 6-hours afteradministration such that the patient has already received a minimaltherapeutic dose at the normal awakening time. The patient thus does notneed to be awakened, given a pill, and then required to have breakfastand prepare for their day prior to experiencing a therapeutic effect.

The present disclosure can be described, therefore, as a method oftreating a condition in a subject with a disorder or conditionresponsive to the administration of a methylphenidate, comprising orallyadministering an effective amount of methylphenidate or a pharmaceuticalsalt thereof in a formulation that when administered to said subjectprovides: (i) a lag period of at least 5 hours during which the plasmaconcentration of methylphenidate is less than 10% of the maximumconcentration (C_(max)); (ii) a plasma area under the curve at 10 hours(AUC₀₋₁₀) after administration that is less than about 7% of AUC₀₋₄₈;and (iii) wherein the time to C_(max) (T_(max)) is between 12 and 19hours after administration and wherein administration to a population ofsubjects provides a significant improvement in ADHD related behavior orability over a period of at least 12 continuous hours as measured by avalidated rating scale. As used herein a validated rating scale is ascale, score or combined score that is validated or published in a peerreviewed journal, or is recognized as valid by those of skill in theart, or considered by a pharmaceutical regulatory agency such as theU.S. Food and Drug Administration or the European Medicines Agency, forexample, as providing a valid measure of therapeutic efficacy.

The validated rating scale, score or combined score as used hereinincludes methods that are recognized by a government pharmaceuticalregulatory agency, are published and/or relied upon in a peer reviewedjournal, or in a clinical trial reported in a peer-reviewed journal orare endorsed by an association of physicians or clinicians. Examples ofsuch methods or measurements include, but are not limited to theADHD-RS-IV scale based on the Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition criteria, the Before School FunctioningQuestionnaire (BSFQ), Clinical Global Impression (CGI), Clinical GlobalImpression of Improvement (CGI-I), Clinical Global Impresssion ofSeverity (CGI-S), Conors Global Index Parent (CGI-P), Diagnostic andStatistical Manual of Mental Disorders—Fourth Edition Text Revision(DSM-IV-TR), Parents Rating of Evening and Morning Behavior Revised(PREMB-R), Permanent Product Measure of Performance (PERMP) scores,Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale, orSKAMP-CS combined score.

The disclosure can be described in certain embodiments as a method inwhich when the formulation is administered to a population of adult,adolescent or pediatric subjects, the formulation provides a significantimprovement over placebo in Permanent Product Measure of Performancescores over a period of at least about 12 continuous hours, theformulation provides a significant improvement over placebo in PermanentProduct Measure of Performance scores over a period from about 11through about 23 hours post-dose, or when the formulation isadministered at about 8-10 PM, the formulation provides a significantimprovement in PERMP scores during a 10-12 hour period from about 7 AMto about 9 PM the following day. In certain embodiments the significantimprovement is at least a 50% improvement over placebo at each hour fora period of 12 hours.

The disclosure can also be described in certain embodiments as a methodin which when the formulation is administered to a population ofadolescent or child subjects, the formulation provides a significantimprovement in SKAMP scores during a period of about 12 continuous hoursand where the formulation provides a significant improvement in SKAMPscores during a period from about 11 through about 23 hours post-dose,or wherein when the formulation is administered at about 8-10 PM, theformulation provides a significant improvement in SKAMP scores during a10-12 hour period from about 7 AM to about 9 PM the following day.

The present disclosure can also be described in certain embodiments as amethod of treating attention deficit disorder or attention deficithyperactivity disorder in a subject comprising orally administering tothe subject a unit dose of methylphenidate or a pharmaceutical saltthereof in a unit dose that comprises a sustained release formulationcomprising the methylphenidate or a pharmaceutical salt thereof enclosedin an outer coating that is insoluble in an aqueous medium at pH below5.5, wherein the unit dose provides a lag period of at least 5 hoursduring which the subject's plasma concentration of methylphenidate or isless than 10% of the maximum concentration (C_(max)), wherein the plasmaarea under the curve at 10 hours (AUC₀₋₁₀) after administration is lessthan about 7% of AUC₀₋₄₈, wherein the time to C_(max) (T_(max)) isbetween 12 and 19 hours after administration, and wherein administrationto a population of subjects provides a significant improvement in ADHDrelated behavior or cognitive ability over a period of at least 12continuous hours.

The validated rating scale, score or combined score as used hereinincludes methods that are recognized by a government pharmaceuticalregulatory agency, are published and/or relied upon in a peer reviewedjournal, or in a clinical trial reported in a peer-reviewed journal orare endorsed by an association of physicians or clinicians. Examples ofsuch methods or measurements include, but are not limited to theADHD-RS-IV scale based on the Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition criteria, the Before School FunctioningQuestionnaire (BSFQ), Clinical Global Impression (CGI), Clinical GlobalImpression of Improvement (CGI-I), Clinical Global Impresssion ofSeverity (CGI-S), Conors Global Index Parent (CGI-P), Diagnostic andStatistical Manual of Mental Disorders—Fourth Edition Text Revision(DSM-IV-TR), Parents Rating of Evening and Morning Behavior Revised(PREMB-R), Permanent Product Measure of Performance (PERMP) scores,Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale, orSKAMP-CS combined score.

The disclosure can be described in certain embodiments as a method inwhich when the formulation is administered to a population of adult,adolescent or pediatric subjects, the formulation provides a significantimprovement over placebo in Permanent Product Measure of Performancescores over a period of at least about 12 continuous hours, theformulation provides a significant improvement over placebo in PermanentProduct Measure of Performance scores over a period from about 11through about 23 hours post-dose, or when the formulation isadministered at about 8-10 PM, the formulation provides a significantimprovement in PERMP scores during a 10-12 hour period from about 7 AMto about 9 PM the following day. In certain embodiments the significantimprovement is at least a 50% improvement over placebo at each hour fora period of 12 hours.

The disclosure can also be described in certain embodiments as a methodin which when the formulation is administered to a population ofadolescent or child subjects, the formulation provides a significantimprovement in SKAMP scores during a period of about 12 continuous hoursand where the formulation provides a significant improvement in SKAMPscores during a period from about 11 through about 23 hours post-dose,or wherein when the formulation is administered at about 8-10 PM, theformulation provides a significant improvement in SKAMP scores during a10-12 hour period from about 7 AM to about 9 PM the following day.

The formulations disclosed herein also provide an ascending release ofthe drug over the next 8-16 hours or so after the delay period, or up to16 hours after administration of the dosage forms. The dosage forms thuscan provide a delayed release followed by a sigmoidal release curve asshown in the accompanying drawings, FIG. 5.

CNS Stimulants

Stimulant medications (e.g., methylphenidate and amphetamines andprodrugs) are often prescribed to treat individuals diagnosed with ADHD.According to the National Institute of Health, all stimulants work byincreasing dopamine levels in the brain. Dopamine is a brain chemical(or neurotransmitter) associated with pleasure, movement, and attention.The therapeutic effect of stimulants is achieved by slow and steadyincreases of dopamine, which are similar to the natural production bythe brain. The doses prescribed by physicians start low and increasegradually until a therapeutic effect is reached.

Treatment of ADHD with stimulants, often in conjunction withpsychotherapy, helps to improve the symptoms of ADHD, as well as theself-esteem, cognition, and social and family interactions of thepatient. The most commonly prescribed medications include amphetaminesand methylphenidate. These medications have a paradoxically calming and“focusing” effect on individuals with ADHD. Researchers speculate thatbecause methylphenidate amplifies the release of dopamine, it canimprove attention and focus in individuals who have dopamine signalsthat are weak.

Amphetamines that are useful in the disclosed formulations and methodsinclude amphetamine and its isomers such as dextroamphetamine, d,lamphetamines and their pharmaceutically acceptable salts, such assulfate, saccharate, and aspartate salts, for example. Amphetamines arenon-catecholamine, sympathomimetic amines with CNS stimulant activity.Peripheral actions include elevations of systolic and diastolic bloodpressures and weak bronchodilator and respiratory stimulant action.

Dextroamphetamine is the dextro isomer of the compound d,l-amphetaminesulfate, a sympathomimetic amine of the amphetamine group. Chemically,dextroamphetamine is d-alpha-methylphenethylamine. Dextroamphetamine canbe used in the practice of the present disclosure, or variouspharmaceutically acceptable salts of dextroamphetamine can be used.

Methylphenidate

Methylphenidate is another CNS (CNS) stimulant that was approved by theFDA in 1955 for the hypeactivity. Methylphenidate can be prescribed in aracemic mix of dextro and levo conformations or as the pure dextroisomer. Methylphenidate has two chiral centers in the molecule and thuscan also be further refined to enrich the d threo isomer. The use ofpharmaceutically acceptable salts of methylphenidate, such asmethylphenidate hydrochloride is also contemplated by the presentdisclosure.

It is understood that the active pharmaceutical ingredients of thepresent disclosure can be present as prodrugs that are activated in thebody of a user. One form of prodrug has an amino acid conjugated to theactive ingredient. When the amino acid is enzymatically cleaved, theactive drug is released. Prodrugs comprising a lysyl, isoleucyl oraspartyl conjugate are contemplated to be useful in the practice of thepresent disclosure.

Formulations

The formulations of the disclosure are designed to provide novel releaseand plasma profiles that include a first lag phase followed by asigmoidal release phase. By providing this profile, the dosage formsprovide a timed, prolonged therapeutic effect when taken once a day.Based on the release characteristics, in which the dosage form passesthrough the stomach prior to release, the formulations disclosed hereinprovide at least the following further advantages: low variability ingastric emptying, low risk of sudden dose dumping, low incidence ofgastric discomfort and low intra- and inter-individual variability.

A first example of a dosage form is a single population of beads thatcan be administered in a capsule or a liquid or gel suspensioncontaining the beads. An example of a bead structure 10 is shown inschematic form in FIG. 1A-B. In FIG. 1A, the inner circle represents adrug containing core, which includes the active ingredient or pro-drug,the appropriate excipients and optionally a superdisintegrant orosmagent. A core can include, for example, an active agent, adisintegrant, osmagent, or pore-forming agent, and a binder. Anexemplary core includes about 20-25% active agent, about 45-60%microcrystalline cellulose, about 10-30% potassium chloride and about3-5% binder such as polyvinyl pyrrolidone or hydroxypropyl cellulose,for example. The drug containing core can be made by a variety ofprocesses known in the art, including wet granulation, extrusion, andspheronization. In this embodiment, two layers cover the core. The firstlayer is a sustained release layer and the outer layer is a delayedrelease layer that is optionally pH dependent. In certain embodiments,the core as shown in FIG. 1A can be an inert non-pareil bead. The innercore is a bead of sugar and starch or it can be composed ofmicrocrystalline cellulose. Any spherical bead that is suitable forforming the core bead and is pharmaceutically acceptable can be used. Insuch embodiments, the drug and excipients of the core are layered ontothe core bead, providing a three layer formulation.

The outermost layer 14 is a delayed release or an enteric coating. Incertain embodiments this layer comprises a water-soluble polymer, awater-insoluble polymer, a plasticizer and a lubricant. The time ofdelay of drug release is controlled by the ratio of water-soluble andinsoluble polymers, the plasticizer concentration, amount of lubricant,and the coating weight gain, which can be up to 35-45%. Alternativelythis layer is a pH dependent polymer that dissolves at pH above 5.5.

A sustained release layer 16 is designed to provide a slower initialrate of release that increases over a period of up to 8-10 hours afterthe layer is exposed to an aqueous environment. The increasing drugprofile can be achieved by a membrane that becomes more permeable overtime. An example of a sustained release layer includes a water-solublepolymer, a water-insoluble polymer, a plasticizer and a lubricant. Therate of drug release can be controlled or sustained by varying the ratioof water-soluble and water-insoluble polymers and by varying the coatingthickness up to 15-45% weight gain.

An alternative embodiment is shown in FIG. 1B. In this figure, aswellable layer 18, including a superdisintegrant or osmotic agent isdisposed between the core and the sustained release layer.

In certain embodiments, the compositions and methods of the presentdisclosure include a formulation of 4 layers 30 as shown in FIG. 3. Thisformulation can include an inner core 15 of a non-pareil bead and 4concentric layers from inner to outer described as, a swelling polymerlayer 18, drug layer 12, a sustained release layer 16 and a pH dependentdelayed release layer 14, which can be a pH dependent layer.

In certain embodiments, the 4 layer composition can be made in astep-wise fashion. In the first step, a hydrophilic polymer suspended inethanol with a binder is coated onto nonpareil beads to a 30-50% weightgain. In certain embodiments PolyOx Coagulant SFP (PEO) marketed by theDow Chemical Company is the hydrophilic polymer and hydroxypropylcellulose (HPC LF) is added as the binder. The PolyOx layer is thensealed with a hydroxypropyl cellulose such as Klucel® EF to a 10% weightgain. The active pharmaceutical ingredient (API) is then suspended inethanol with a binder and coated onto the layered bead and the sustainedrelease and delayed release coatings are applied as described herein.

FIGS. 2A-B represent embodiments in which the core is a minitablet 20rather than a bead. The core and layers in FIGS. 2A and B arefunctionally the same as the like numbered layers on the beads in FIG.1A-B, except there is no optional inert core.

Various water-soluble polymers can be used in the disclosedformulations. Such polymers include, but are not limited to polyethyleneoxide (PEO), ethylene oxide-propylene oxide co-polymers,polyethylene-polypropylene glycol (e.g. poloxamer), carbomer,polycarbophil, chitosan, polyvinyl pyrrolidone (PVP), polyvinyl alcohol(PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC),hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, methylcellulose,hydroxyethyl methylcellulose, hydroxypropyl methylcellulose,polyacrylates such as carbomer, polyacrylamides, polymethacrylamides,polyphosphazines, polyoxazolidines, polyhydroxyalkylcarboxylic acids,alginic acid and its derivatives such as carrageenate alginates,ammonium alginate and sodium alginate, starch and starch derivatives,polysaccharides, carboxypolymethylene, polyethylene glycol, natural gumssuch as gum guar, gum acacia, gum tragacanth, karaya gum and gumxanthan, povidone, gelatin or the like.

In certain embodiments, at least the delayed release layer includes oneor more polymers such as an acrylic polymer, acrylic copolymer,methacrylic polymer or methacrylic copolymer, including but not limitedto Eudragit® L100, Eudragit® L100-55, Eudragit® L 30 D-55, Eudragit®S100, Eudragit® 4135F, Eudragit® RS, acrylic acid and methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkylamine copolymer, polymethyl methacrylate,polymethacrylic acid anhydride, polymethacrylate, polyacrylamide,polymethacrylic acid anhydride and glycidyl methacrylate copolymers, analkylcellulose such as ethylcellulose, methylcellulose, calciumcarboxymethyl cellulose, certain substituted cellulose polymers such ashydroxypropyl methylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, celluloseacetate phthalate, and cellulose acetate trimaleate, polyvinyl acetatephthalate, polyester, waxes, shellac, zein, or the like.

Eudragits are well known polymers and copolymers useful for controlledrelease applications. The EUDRAGIT® grades for enteric coatings arebased on anionic polymers of methacrylic acid and methacrylates. Theycontain —COOH as a functional group. They dissolve at ranges from pH 5.5to pH 7. EUDRAGIT® FS 30 D is the aqueous dispersion of an anioniccopolymer based on methyl acrylate, methyl methacrylate and methacrylicacid. It is insoluble in acidic media, but dissolves by salt formationabove pH 7.0. Eudragit L100-55 and L30-55 dissolve at pH above 5.5.Eudragit L100 and S100 dissolve at pH above 6.0.

Sustained-release EUDRAGIT® formulations are employed for many oraldosage forms to enable time-controlled release of active ingredients.Drug delivery can be controlled throughout the whole gastro-intestinaltract for increased therapeutic effect and patient compliance. Differentpolymer combinations of EUDRAGIT® RL (readily permeable) and RS(sparingly permeable) grades allow custom-tailored release profiles andenable a wide range of alternatives to achieve the desired drug deliveryperformance. The EUDRAGIT® NE polymer is a neutral ester dispersionwhich requires no plasticizer and is particularly suitable forgranulation processes in the manufacture of matrix tablets and sustainedrelease coatings.

Exemplary osmagents or osmotic agents include organic and inorganiccompounds such as salts, acids, bases, chelating agents, sodiumchloride, lithium chloride, magnesium chloride, magnesium sulfate,lithium sulfate, potassium chloride, sodium sulfite, calciumbicarbonate, sodium sulfate, calcium sulfate, calcium lactate,d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactosemonohydrate, glucose, combinations thereof and other similar orequivalent materials which are widely known in the art.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of a solid mass(layer) into smaller particles that are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays,bentonite, microcrystalline cellulose (e.g., Avicel™),carboxymethylcellulose calcium, croscarmellose sodium, alginic acid,sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite™),alginates, sodium starch glycolate, gums, agar, guar, locust bean,karaya, pectin, tragacanth, crospovidone and other materials known toone of ordinary skill in the art. A superdisintegrant is a rapidlyacting disintegrant. Exemplary superdisintegrants include crospovidoneand low substituted HPC.

In preferred embodiments, a plasticizer is also included in the oraldosage form. Plasticizers suitable for use in the present inventioninclude, but are not limited to, low molecular weight polymers,oligomers, copolymers, oils, small organic molecules, low molecularweight polyols having aliphatic hydroxyls, ester-type plasticizers,glycol ethers, poly(propylene glycol), multi-block polymers, singleblock polymers, low molecular weight poly(ethylene glycol), citrateester-type plasticizers, triacetin, propylene glycol and glycerin. Suchplasticizers can also include ethylene glycol, 1,2-butylene glycol,2,3-butylene glycol, styrene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol and other poly(ethylene glycol) compounds,monopropylene glycol monoisopropyl ether, propylene glycol monoethylether, ethylene glycol monoethyl ether, diethylene glycol monoethylether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,dibutyl sebacate, acetyltributylcitrate, triethyl citrate, acetyltriethyl citrate, tributyl citrate and allyl glycolate.

It is an aspect of the compositions and methods of the presentdisclosure that the formulations or dosage forms can also incorporateone or more ingredients that discourage or prevent abuse of the activeingredients by crushing and inhaling a powdered form of theformulations. As such, a nasal irritant can be included, either as aseparate layer, or incorporated into an outer layer, a sustained releaselayer or the core of the dosage forms. Exemplary irritants include, butare not limited to sodium lauryl sulfate, which is also called sodiumdodecyl sulfate or capsaicinoids including capsaicin and syntheticcapsaicins. In certain embodiments, the dosage forms include from 1% to10% sodium lauryl sulfate.

The compositions of the present disclosure can also include one or morefunctional excipients such as lubricants, thermal lubricants,antioxidants, buffering agents, alkalinizing agents, binders, diluents,sweeteners, chelating agents, colorants, flavorants, surfactants,solubilizers, wetting agents, stabilizers, hydrophilic polymers,hydrophobic polymers, waxes, lipophilic materials, absorption enhancers,preservatives, absorbents, cross-linking agents, bioadhesive polymers,retardants, pore formers, and fragrance.

Lubricants or thermal lubricants useful in the present inventioninclude, but are not limited to fatty esters, glyceryl monooleate,glyceryl monostearate, wax, carnauba wax, beeswax, vitamin E succinate,and a combination thereof.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by oxidation due to the presence of oxygen free radicals orfree metals in the composition. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),hypophophorous acid, monothioglycerol, sodium ascorbate, sodiumformaldehyde sulfoxylate and sodium metabisulfite and others known tothose of ordinary skill in the art. Other suitable antioxidants include,for example, vitamin C, sodium bisulfite, vitamin E and its derivatives,propyl gallate or a sulfite derivative.

Binders suitable for use in the present invention include beeswax,carnauba wax, cetyl palmitate, glycerol behenate, glyceryl monostearate,glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil,microcrystalline wax, paraffin wax, stearic acid, stearic alcohol,stearate 6000 WL1644, gelucire 50/13, poloxamer 188, and polyethyleneglycol (PEG) 2000, 3000, 6000, 8000, 10000 or 20000.

A buffering agent is used to resist change in pH upon dilution oraddition of acid or alkali. Such compounds include, by way of exampleand without limitation, potassium metaphosphate, potassium phosphate,monobasic sodium acetate and sodium citrate anhydrous and dihydrate,salts of inorganic or organic acids, salts of inorganic or organicbases, and others known to those of ordinary skill in the art,

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, and trolamine and othersknown to those of ordinary skill in the art.

Exemplary binders include: polyethylene oxide; polypropylene oxide;polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate andmethacrylate copolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcelluloses and cellulosicderivatives such as low substituted HPC (L-HPC), methylcellulose;hydroxyalkylcelluloses such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, andhydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; starches, pectins;PLA and PLGA, polyesters (shellac), wax such as carnauba wax, beeswax;polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, andxanthan gum.

Exemplary chelating agents include EDTA and its salts, alphahydroxyacids such as citric acid, polycarboxylic acids, polyamines, derivativesthereof, and others known to those of ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors that have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors will bepresent in any amount as desired by those of ordinary skill in the art.Particular flavors are the grape and cherry flavors and citrus flavorssuch as orange.

Suitable surfactants include Polysorbate 80, sorbitan monooleate,polyoxymer, sodium lauryl sulfate or others known in the art. Soaps andsynthetic detergents may be employed as surfactants. Suitable soapsinclude fatty acid alkali metal, ammonium, and triethanolamine salts.Suitable detergents include cationic detergents, for example, dimethyldialkyl ammonium halides, alkyl pyridinium halides, and alkylamineacetates; anionic detergents, for example, alkyl, aryl and olefinsulfonates, alkyl, olefin, ether and monoglyceride sulfates, andsulfosuccinates; nonionic detergents, for example, fatty amine oxides,fatty acid alkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)copolymers; and amphoteric detergents, for example, alkylβ-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; andmixtures thereof.

A wetting agent is an agent that decreases the surface tension of aliquid. Wetting agents would include alcohols, glycerin, proteins,peptides water miscible solvents such as glycols, hydrophilic polymersPolysorbate 80, sorbitan monooleate, sodium lauryl sulfate, fatty acidalkali metal, ammonium, and triethanolamine salts, dimethyl dialkylammonium halides, alkyl pyridinium halides, and alkylamine acetates;anionic detergents, for example, alkyl, aryl and olefin sulfonates,alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates;nonionic detergents, for example, fatty amine oxides, fatty acidalkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)copolymers; and amphoteric detergents, for example, alkylβ-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; andmixtures thereof.

Solubilizers include cyclodextrins, povidone, combinations thereof, andothers known to those of ordinary skill in the art.

Exemplary waxes include carnauba wax, beeswax, microcrystalline wax andothers known to one of ordinary skill in the art.

Exemplary absorption enhancers include dimethyl sulfoxide, Vitamin EPGS, sodium cholate and others known to one of ordinary skill in theart.

Preservatives include compounds used to prevent the groweighth ofmicroorganisms. Suitable preservatives include, by way of example andwithout limitation, benzalkonium chloride, benzethonium chloride, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate and thimerosal and others known to thoseof ordinary skill in the art.

Examples of absorbents include sodium starch glycolate (Explotab™,Primojel™) and croscarmellose sodium (Ac-Di-Sol™), cross-linked PVP(Polyplasdone™ XL 10), veegum, clays, alginates, PVP, alginic acid,carboxymethylcellulose calcium, microcrystalline cellulose (e.g.,Avicel™), polacrillin potassium (e.g., Amberlite™), sodium alginate,corn starch, potato starch, pregelatinized starch, modified starch,cellulosic agents, montmorrilonite clays (e.g., bentonite), gums, agar,locust bean gum, gum karaya, pectin, tragacanth, and other disintegrantsknown in to those of ordinary skill in the art.

A cross-linking agent is defined as any compound that will formcross-links between the moieties of the polymer. A cross-linking agentcan include, by way of example and without limitation, an organic acid,an alpha-hydroxy acid, and a beta-hydroxy acid. Suitable cross-linkingagents include tartaric acid, citric acid, fumaric acid, succinic acidand others known to those of ordinary skill in the art.

Bioadhesive polymers include polyethylene oxide, KLUCEL(hydroxypropylcellulose), CARBOPOL, polycarbophil, GANTREZ, Poloxamer,and combinations thereof, and others known to one of ordinary skill inthe art.

Retardants are agents that are insoluble or slightly soluble polymerswith a glass transition temperature (Tg) above 45° C., or above 50° C.before being plasticized by other agents in the formulation includingother polymers and other excipients needed for processing. Theexcipients include waxes, acrylics, cellulosics, lipids, proteins,glycols, and the like.

Exemplary pore formers include water-soluble polymers such aspolyethylene glycol, propylene glycol, polaxamer and povidone; binderssuch as lactose, calcium sulfate, calcium phosphate and the like; saltssuch as sodium chloride, magnesium chloride and the like; combinationsthereof and other similar or equivalent materials which are widely knownin the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose andother such materials known to those of ordinary skill in the art.

It should be understood that compounds used in the art of pharmaceuticalformulation generally serve a variety of functions or purposes. Thus, ifa compound named herein is mentioned only once or is used to define morethan one term herein, its purpose or function should not be construed asbeing limited solely to that or those named purpose(s) or function(s).

It is an aspect of the compositions and methods of the presentdisclosure that the disclosed pharmaceutical formulations provide novelrelease profiles in vivo and when orally administered to a human. Theformulations provide a lag time of from 4-12 hours in certainembodiments followed by release of 85% of the drug over the following 9hours in an ascending dose.

The dissolution profile is performed in conditions designed to mimic thegastric environment, or the environment that is encountered by an oralcomposition that is swallowed by a human. Although residence time in thestomach varies, a typical test places the composition in the low pHsolution of 0.1N HCl for two hours to mimic the residence time instomach acid. The composition is then placed in a higher pH aqueoussolution, about pH 6 for hours 2-6 followed by typically pH 6.8 to mimicthe environment of the ileum and colon. As used herein, simulatedgastric conditions encompasses both the acidic first stage and thesubsequent higher pH stages of a normal human gastrointestinal tract.

Following the delay period, the plasma concentration increases overapproximately 9-10 hours to a reach a maximum plasma concentration(C_(max)). Based on this release profile, a dose taken at 9:00 P.M witha 6 hour delay begins to release the drug at about 3 A.M. and themaximum plasma concentration is reached about 16 hours later.

It is a further aspect of the compositions and methods of the presentdisclosure that the drug can begin to be slowly released during the lagtime. This release is determined by the composition of the delayedrelease layer as described herein. Some examples of a small releaseduring the lag time are those in which no more than about 10% of thedrug is released during the 3-12 hour lag. It is also understood that agreater percentage, 12%, 15%, 18% or even 20%, can be released as thedelayed release layer becomes more permeable.

Disclosed herein, therefore, are pharmaceutical preparations for oncedaily administration of a CNS stimulant for treatment of conditions thatrespond to such drugs, such as ADD, ADHD, bipolar depression,narcolepsy, sleeping disorders, and fatigue. The dosage is formulated tobe taken prior to going bed and starts to release after a lag of severalhours so the patient has absorbed a sufficient amount of drug to have atherapeutic effect while awakening and preparing to leave for work orschool. It is a further aspect of the formulations that the drug isreleased in an ascending dose through the day to overcome any acutetolerance effect and maintain a therapeutic level of drug.

An embodiment of the compositions and methods of the present disclosureis a dosage form that includes a capsule enclosing a single populationof beads or minitablets that include a core and 2 or more coatingssurrounding the core. The inner core is a bead or minitablet containingan API and one or more excipients. The core is enclosed in a sustainedrelease layer, and an outer, delayed release layer.

In certain embodiments the sustained release layer includes acombination of water-soluble polymers and water-insoluble polymers. Thesustained release coating can contain a combination of polyethyleneoxide and an ethylcellulose, for example, or a hydroxypropylmethylcellulose and ethylcellulose. An ethylcellulose product that can be usedin the disclosed dosage forms is Ethocel™, marketed under a trade markof The Dow Chemical Company. The rate of dissolution of the sustainedrelease layer can be controlled by adjusting the ratio of water-solublepolymer to water-insoluble polymer in the coating or layer. The weightratio of water-insoluble to water-soluble polymers can be adjusted, forexample and without limitation, from 90:10 to 10:90, from 80:20 to20:80, from 75:25 to 25:75, from 70:30 to 30:70, from 67.5:33.5 to33.5:67.5 from 60:40 to 40:60, from 56:44 to 44:56, or to 50:50.

The sustained release coating can also contain plasticizers such astriethyl citrate (TEC) at levels of from 3% to 50% of the combinedweight of the polymers. Other additives to the coating can includetitanium dioxide, talc, colloidal silicone dioxide or citric acid.

Some examples of sustained release layers are shown in the followingtable. The various formulations include those in which the ratios ofwater-insoluble to water-soluble polymers are varied and one in whichthe ratios are reversed. Citric acid was added to a formula to keep themicro environment pH in the film low to inhibit the dissolution ofHPMCAS-LF, which dissolves at >pH5.5 thus creating a lag at thebeginning of the dissolution curve. In certain embodiments, the activeingredient, or API can be included in the sustained release layer. Ininitial testing metronidazole, a model drug, was micronized and added tothe formulation as a suspension. Any of the appropriate disclosed API'scan be added to the sustained release layer, however.

TABLE 1 Exemplary Sustained Release Layers A B C D E F Component (% w/w)(% w/w) (% w/w) (% w/w) (% w/w) (% w/w) Ethocel 51.0 34.9 34.5 34.4 60.236.1 API 47.2 PEO 36.1 60.2 HPMC E5 P 17.0 13.1 HPMCAS-LF 27.6 11.5 Talc3.6 2.8 3.6 2.4 Titanium 24.0 18.5 24.0 Dioxide Citric acid 6.9Colloidal silicon 0.4 dioxide TEC 4.0 26.2 3.4 4.6 3.6 3.6 Totals* 100.0100.0 100.0 100.0 100.0 100.0 *Figures may not sum to 100, due torounding

An exemplary core was synthesized as shown in Table 2. In this example,an osmotic agent is added to the core.

TABLE 2 Pellet Core Component (% w/w) API 20.0 Avicell PH101 47.0Potassium chloride 30.0 Klucell EF 3.0 Totals 100.0

A sustained release layer with the formula shown in the right handcolumn (F) of Table 1 was synthesized on an API containing bead. Theformula was designated 2009-043-10A when the sustained release layerprovided a 25% weight gain and 2009-043-10 when the sustained releaselayer provided a 35% gain. Additional layers were synthesized as shownin columns A and B of Table 1. In column B, the formula of column A wasmodified such that the colloidal silicon dioxide was removed and theplasticizer was increased to 50% w/w of the polymer level. All of theother ratios as shown in column A were maintained.

The formula of column A was also modified to produce the sustainedrelease layer of column C of Table 1. In this formula, the colloidalsilicon dioxide was removed and citric acid was added. The ratio ofEthocel:HPMCAS was decreased from 75:25 to 56:44. This formula wasexpected to provide a lower pH in the microenvironment to increase thelag time. A sample layered to produce a 25% weight gain and anothersample with a 45% weight gain were subjected to dissolution testing.

Another embodiment of a sustained release layer was produced in whichthe drug or API was included in the sustained release layer. This layeris described in column D of Table 1. In this formula, the ratio betweenEthocel and HPMCAS was 75:25. A micronized drug was added to the formulaas a suspension. A sample with a 25% weight gain was subjected todissolution testing.

Core tablets as described in Table 2 were coated with a sustainedrelease layer formulated as in column A of Table 1. This formulationexhibited an initial slow drug release (3% in the first 3 hours).

Another embodiment of a sustained release coating was designed withpolyethyleneoxide (PEO) to ethyl cellulose ratio of 37.5:62.5. Talc wasalso added to one sample at 10% to improve the coating process. Thepresence of talc did not affect drug release. The release profiles forthese formulations processed with a 25% weight gain and a 40% weightgain were also determined. The formulations exhibited a 1 hour lag andthe drug was substantially completely released within 9 hours.

While the disclosed compositions of a capsule containing a singlepopulation of beads or minitablets with a sustained release layer and anouter, delayed release layer are shown here in to be an effectivedelivery system with novel release characteristics and surprisingly lowvariability in absorption when administered to humans, it is understoodthat alternative compositions can be used in light of the presentdisclosure.

In certain embodiments a drug containing core bead or minitablet iscoated with a delayed release layer that includes one or morewater-insoluble polymers, one or more water-soluble polymers and asilicone oil to achieve a desired delay or lag time prior to release asin the present disclosure. Lag time and release are controlled by theproportion of the two types of polymers and the thickness of the layer.In such embodiments, the delayed release layer can include, but is notlimited to cellulose acetate phthalate, cellulose acetate trimaletate,hydroxyl propyl methylcellulose phthalate, polyvinyl acetate phthalate,acrylic polymers, polyvinyl acetaldiethylamino acetate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate,shellac, methacrylic acid copolymers, Eudragit L30D, Eudragit L100,Eudragit FS30D, Eudragit S100 or combinations of any thereof. Thedelayed release layer can also include a plasticizer, or in certainembodiments the delayed release layer can include methacrylic acidcopolymer Type B, mono- and diglycerides, dibutyl sebacate andpolysorbate 80. The delayed release layer can also include a celluloseether derivative, an acrylic resin, a copolymer of acrylic acid andmethacrylic acid esters with quaternary ammonium groups, a copolymer ofacrylic acid and methacrylic acid esters or a combination of anythereof. The layer can further include a powder component such as talcas a carrier for the silicone oil.

In certain embodiments of the invention, a CNS stimulant can becontained in a delayed and/or controlled release capsule. In suchembodiments a water-insoluble capsule contains one or more compartmentsin which the drug or active agent is held. Additionally one or moreabsorbents, superabsorbents or osmagents are included in the drugcontaining compartments. The capsules also include one more aperturesplugged with a water-soluble polymer, at least one in fluidcommunication with each compartment and a delayed release layerenclosing the entire capsule.

In such embodiments the length of initial delay can be controlled by thecomposition and thickness of the outer, delayed release layer. Thislayer can be a pH dependent layer or a pH independent layer as disclosedherein. When the capsule is administered to a human, the delayed releaselayer begins to lose integrity as the capsule passes through the GItract. When the water-soluble plugs are exposed and dissolve, aqueousfluid enters the drug containing compartment(s) and is absorbed by theabsorbent or osmagent, thus driving the active agent from the capsulethrough the aperture. The release profile can be controlled by theconcentration and absorption characteristics of the absorbent orosmagent to obtain the desired profile.

Sustained Release Coatings on Dextroamphetamine Sulfate Pellets

Formulations of the disclosure are made in which hydrophobic excipientsare introduced to give an added delay in the drug release. Theplasticizer level is kept at 7.26% of the Ethocel™ level. Theformulations are described in Table 3.

TABLE 3 Sustained Release Formulations Lot Number 2009-066-512009-066-53 2009-066-59 2009-066-64 2009-066-67 2009-066-69 2009-066-722009-066-75 2009-066-78 Component % W/W Ethocel ™ Std. 10 55.8 55.8 38.543.0 45.4 55.9 53.2 50.7 45.4 Klucel ™ (EF) 8.9 8.9 6.1 1.3 11.3 2.9 5.611.3 Triethyl Citrate 2.6 2.6 2.8 3.1 3.3 Imperial Talc 500 52.6 DibutylSebacate 4.1 3.9 3.7 3.3 Magnesium 52.6 52.6 52.6 40.0 40.0 40.0 40.040.0 Stearate

These formulations were coated to a 30% weight gain level and sampleswere submitted for testing at 10 mg free base capsule dose. Thedissolution testing took place in pH 7.0 buffer with a paddle speed of75 rpm.

Lot 2009-066-51 has a water-insoluble to water-soluble ratio of 80:20.This results in a significantly faster release profile. The API releases25% in the first hour. In further formulations talc was removed andreplaced with magnesium stearate.

In Lot 2009-066-53, which contained magnesium stearate, the initialrelease was significantly slower. Further changes included increasingthe Ethocel™ level in Lot -59 and -64 while decreasing the Klucel®level. The ratio of Ethocel™ to Klucel® in Lot -59 and -64 respectfullyis 86:14 and 97:3. This change was expected to slow the release from Lot53, but the dissolution release time actually increased. Lot -67included a decrease of the magnesium stearate and decrease in theEthocel™ to Klucel® ratio (back to 80:20). This resulted in a releasefaster than the model profile.

Replacement of the hydrophilic plasticizer TEC with dibutyl sebacate(DBS), a hydrophobic plasticizer resulted in a significantly longerdelay prior to initial release. Lot 2009-066-69 was the first lotutilizing DBS as a plasticizer. With the addition of DBS and the removalof Klucel®, the initial drug release was less than 2% over 8 hours.

Klucel® was added back into the formulation in Lot 2009-066-72. Theratio of Ethocel™ to Klucel® was 95:5. The dissolution profile wassimilar to Lot 2009-066-69. In Lot 2009-066-75, the ratio of Ethocel™ toKlucel® decreased from 95:5 to 90:10. This change did not result in adifferent release profile compared to the two previous formulations.

For Lot 2009-066-78, the ratio of Ethocel™ to Klucel® was decreased to80:20, for a higher level of water-soluble polymer. Formulation2009-066-78 exhibited a 20% drug release over 4 hours followed by anincreasing release until over 80% release.

DOE Sustained Release Coatings

A design of experiment (DOE) was set up with three ratios of Ethocel™ toKlucel® ratios: 70:30, 75:25, and 80:20. The coatings were applied inthe GPCG2 with a 1.0 mm spray nozzle. For a DOE coating run 650.0 g ofpellets were used. The pellets consisted of 80% w/w placebo pellets and20% Dextroamphetamine sulfate pellets. The pellets were diluted toconserve the D-amphetamine sulfate pellets. The DOE formulations areshown in Table 4. Each coating formulation contained 12% solids w/w. Thesolvents consisted of ethanol to DI water at a ratio of 95:5.

TABLE 4 DOE Formulations Lot Number 2009- 2009- 2009- 2009- 2009- 2009-2009- 2009- 2009- 2009- 2009- 104-13 104-17 104-44 104-48 104-52 104-55104-58 104-61 104-81 138-12 138-29 DOE Run 1 2 3 4 5 6 7 8 9 10 11Component % W/W Ethocel ™ 41.18 36.64 49.15 39.29 34.84 43.30 41.5946.43 41.86 57.58 44.08 Std. 10 Klucel ® 17.65 15.70 12.29 9.82 14.9318.56 10.40 11.61 13.95 14.39 11.02 (EF) Dibutyl 6.18 2.66 3.56 5.895.23 3.14 3.02 6.96 4.19 3.03 4.91 Sebacate Magnesium 35.00 45.00 35.0045.00 45.00 35.00 45.00 35.00 40.00 25.00 40.00 Stearate

Each of the DOE formulations was coated to 30% weight gain, then sampleswere loaded into capsules at 13.6 mg dose (equivalent to 10.0 mg freebase dose), and submitted for dissolution testing in pH 7.2 phosphatebuffer with a paddle speed of 75 rpm.

A standard mixing procedure was developed for the sustained releasedcoating preparations as follows. Charge the ethanol into an appropriatesized beaker. Place the beaker under a lab mixer with a Cowles bladeattached. Create a vortex by increasing the mixing speed and charge theEthocel™, Klucel®, and DBS into the ethanol. The speed of the mixer isturned down so there is no vortex and the excipients mixed untildissolved. Once the excipients dissolve, a vortex can be created for theaddition of the magnesium stearate. The magnesium stearate is mixed fora minimum of 30 minutes or until no agglomerates are present. Adding theDI water to the mixing dispersion is the last step of the process. Thefirst eight DOE dissolution profiles are shown in FIG. 4.

As shown in FIG. 5, DOE 9 had an Ethocel™ to Klucel® ratio of 75:25 andproduced a faster dissolution release. In DOE 10 the Ethocel™ to Klucel®ratio was 80:20 and the magnesium stearate level was decreased from 40%w/w/to 25% w/w. By making these changes, the dissolution profile shiftsto the right far beyond the model profile. The DOE 11 formulation issimilar to Lot 2009-066-78 (see Table 3 and Table 4 for formulations).DOE 11, 3, and 4 have release profiles that are close to the modelprofile. All three have an Ethocel™ to Klucel® ratio of 80:20, butdiffer in percent w/w of the hydrophobic excipients. The DOE 3 coatingwas the closest profile to the model.

Stability of DOE 3 and DOE 4

For a stability study, 13.6 mg (equivalent to 10.0 mg free base dose)dose capsules were loaded into HDPE bottles and loaded into thefollowing stability chambers for the study: 40° C./75% RH, 25° C./60%RH, and 30° C./65% RH. Pellets were also loaded into HDPE bottles withno capsules at 40° C./75% RH for an open container study. After 2 and 4weeks for the open container study at 40° C./75% RH dissolution testingof the pellets took place in pH 7.2 phosphate buffer. The dissolutionresults are shown in FIG. 6 and FIG. 7.

All of the dissolution profiles from the different stability time pointshad similar drug release profiles, demonstrating that the sustainedrelease coatings are stable. The next step in the development was to adda pH dependent coating on top of the sustained release coating.

pH Dependent Coatings

For the pH dependent coatings studies, the DOE 3 pellets were used.Samples of 13.6 mg dose (10.0 mg free base dose) were loaded intocapsules. The dissolution testing took place for 2 hours (T=0-2 hour) in0.1N HCl, then in pH 6.0 phosphate buffer for 4 hours (T=2-6 hour), andfinally in pH 7.0 phosphate buffer for the remaining time. Theformulations are shown in Table 5.

TABLE 5 pH dependent Formulations Lot Number 2009- 2009- 2009-104- 2009-2009- 104-76 104-78 92¹ 138-22 138-25 Component % W/W Eudragit ® S 10060.6 60.0 76.9 80.6 Eudragit ® FS 30 D 64.5 Triethyl Citrate 9.1 3.2 9.1Dibutyl Sebacate 7.7 8.1 Magnesium 15.4 Stearate ImperialTalc 500 30.332.3 30.3 Imwitor ® 900 K 8.1 Tween ® 80 3.2 ¹Same formulation as Lot2009-104-76, but coated at a product temperature 4° C. higher.

The S 100 coatings are made with alcohol/DI water as the solvent at94.4% w/w to 5.6% w/w and the FS 30 D coating is aqueous only. Thedissolution profiles are shown in FIG. 8.

Lot 2009-104-78 exhibited a delay of 6 hours followed by a fast release.The S 100 formulation with GMS (Imwitor 900 K) at 10% w/w was thencoated on the DOE 3 pellets. Lot 2009-138-25B exhibits a delay at thestart of the drug release followed by a release curve that is similar tothe model profile.

pH Dependent/SR Coated DOE 3 Pellets

The study with a pH dependent coating on the DOE 3 SR coating wasrepeated with a 100% active core pellet batch (no placebo pellets). Thecoating parameters are shown in Table 6.

TABLE 6 Lot 2009-138-32 Coating Parameters Parameters Ranges ProductTemperature 32.0-33.0° C. Inlet Temperature 48.4-54.1° C. ExhaustTemperature 29.3-30° C.   Process Air 40-53 m³/h Atomization Air 2.0 BarSpray Time 126.75 min Spray Rate 12.8 g/min

The dissolution profiles of the active and placebo diluted pellets ofthe DOE 3 coatings are shown in FIG. 9.

The pH dependent coating (Lot 2009-138-45) containing GMS was thencoated on the sustained release DOE 3 coating. The pellets were coatedto a 30% weight gain with a sample pulled at 25% weight gain. Thepellets were dosed into 13.6 mg capsules (10.0 mg freebase) and testedin the 3-stage dissolution study. The coating parameters are in Table 7and the dissolution profiles are shown in FIG. 10.

TABLE 7 Lot 2009-138-45 Coating Parameters Parameters Ranges Product32.0-33.0° C. Temperature Inlet Temperature 48.4-54.1° C. Exhaust29.3-30° C.   Temperature Process Air 40-53 m³/h Atomization Air 2.0 BarSpray Time 126.75 min Spray Rate 12.8 g/min

At the 10-hour time point, DOE 3 had released 20% of the drug, closelymatching the target profile. A portion of the pellets from DOE 3 (Lot2009-138-45) were encapsulated to 13.6 mg dose (equivalent to 10 mg freebase dose) in gelatin capsules and placed on stability. Bottles werefilled with 16 capsules and placed in the following conditions: 4bottles at 40° C./75% relative humidity, 4 bottles at 30° C./65%relative humidity, 1 bottle at 25° C./60% relative humidity. Two bottlesjust containing pellets equivalent to 16 capsules were placed in 40°C./75% relative humidity for an open dish accelerated study. After beingin stability for two weeks samples were pulled from open container, 30°C./65% relative humidity, and 40° C./75% relative humidity. Thedissolution profiles for these samples are shown in FIG. 11.

The two-week open container pellets started to release the drug at the4-hour time point. The initial pellets and the other closed containersamples did not start drug release until after the 6-hour time point.The two closed container samples released the drug slower than theinitial release. It was presumed that pellets were absorbing moisturecausing the GMS (Imwitor®) to become unstable and releasing the drugfaster in the open container study. To try to stabilize the GMS, samplesfrom Lot 2009-138-45 were placed in an oven and cured for 12 hours, 24hours, and 48 hours at 50° C. The dissolution results are located inFIG. 12.

At 50° C., the curing time did not affect the drug release. Anothercuring study was set up with the oven set at 55° C. Samples from Lot2009-138-45 (DOE 3) were cured for 24, 48, and 108 hours (4.5 days). Thedissolution profiles are shown in FIG. 13.

The release of drug after curing the pellets at 55° C. was not directlydependent on time. For the samples cured at 55° C., the pellets weredosed (13.6 mg/10.0 mg free base dose) into gelatin and HPMC capsules.The HPMC capsules contain a one-gram desiccant in each bottle to absorbany excess moisture. The samples were cured at 50° C. dosed only in theHPMC capsules with the one-gram desiccant in each bottle. Sixteencapsules were loaded into each bottle. The stability conditions areshown in Table 8.

TABLE 8 Stability Conditions for Cured Pellets Stability Conditions 40°C./ 75% RH (Pellets only 40° C./ 30° C./ 25° C./ Open 75% RH 65% RH 60%RH Container) Capsule Type Number of Bottles per Condition HPMC at 55°C. 4 4 1 2 Gelatin at 55° C. 4 4 1 HPMC at 50° C. 4 4 1 2

After 2 and 4 weeks, the samples cured at 55° C. were pulled anddissolution testing performed on them. The dissolution results for thestability samples are shown in FIG. 14.

For pellets cured at 55° C. loaded into the HPMC capsules thedissolution profile for the initial, 2-week, and 4-week samples gavesimilar results. This demonstrates product stability under thoseconditions. The gelatin-loaded capsules produced a dissolution profile alittle slower than the initial release at 2- and 4-week samples.

Lot 2009-138-45 (DOE 3, SR and pH Coated) containing HPMC capsules withdesiccant was left on stability 40° C./75% RH (closed container) for 8months. Samples were pulled at 2, 3, and 8 months for dissolutiontesting. The dissolution profiles for the HPMC capsules containing theD-amphetamine sulfate pellets are shown in FIG. 15.

After 8 months in accelerated stability, the D-amphetamine sulfate has asimilar profile to the initial release profile (T=0). The onlydifference is a slower release between hours 7-10.

Example 1

An example of a core pellet as described herein contains the followingcomponents as produced in a 5 kg batch.

Batch size 5,000 grams

Granulation Medium Solids 6%

TABLE 9 Component mg/1 mg pellet % w/w g/batch Dextroamphetamine 22.022.0 1100.0 Sulfate, USP Avicel PH-101 65.0 65.0 3250.0 Starch 1500 10.010.0 500.0 Methocel E5 P LV¹ 3.0 3.0 150.0 Total 10.0 100.0 5000.0 DIWater removed during processing 2356.0

In processing the extra water is added into the granulation medium.Water is 47.12% of the dry blend batch size. The granulation medium is2506.0 grams and the spray rate is 418±20 g/min.

Example 2

An example of a sustained release coating to be applied to the corepellet is prepared with the following components.

Core batch size—1100.0 g

Coating weight gain—30%

Solids—12.0%

TABLE 10 Component mg/1 g pellet solvent ratio % w/w g/batch Ethocel S10 14.75 49.15 162.2 Klucel EF 3.69 12.29 40.6 Dibutyl Sebacate 1.073.56 11.7 Mag Stearate 2257 10.50 35.00 115.5 100.00 330.0 Ethanol 952299.0 DI Water 5 121.0 Theoretical amount of coated pellets (g) 1430

Example 3

An S100 pH dependent coating formulated for a 30% weight gain isformulated with the following components.

Coating weight gain—30%

Solids—10.0%

Batch size—715 g

Core pellet amount—550 g

TABLE 11 Component mg/1 g pellet solvent ratio % w/w g/batch EudragitS100 24.18 80.6 133.0 Imwitor 900K 2.43 8.1 13.4 Dibutyl Sebacate 2.438.1 13.4 Tween 80 0.96 3.2 5.3 Ethanol 94.4 1402.5 DI Water 5.6 82.5100.0 1650.0 Theoretical amount of coated pellets 880.0 (g)

Example 4

An S100 pH dependent coating formulated for a 50% weight gain containsthe following components.

Coating weight gain—50.0%

Solids—10.0%

Batch size—715 g

Core pellet amount—550 g

TABLE 12 Component mg/1 g pellet solvent ratio % w/w g/batch EudragitS100 40.30 80.6 221.7 Imwitor 900K 4.05 8.1 22.3 Dibutyl Sebacate 4.058.1 22.3 Tween 80 1.60 3.2 8.8 Ethanol 94.4 2337.5 DI Water 5.6 137.5100.0 2750.0 Theoretical amount of coated pellets (g) 990.0

Example 5

A formulation was made with a pellet core as in Example 1, a sustainedrelease coating as in Example 2 and a pH dependent coating with a 30%weight gain as in Example 3.

TABLE 13 Component mg/1 g pellet % w/w Dextroamphetamine Sulfate USP22.00 13.75 Avicel PH-101 65.00 40.63 Starch 1500 10.00 6.25 Methocel E5P LV¹ 3.00 1.88 Ethocel Std 10 14.75 9.22 Klucel EF 3.69 2.30 DibutylSebacate 1.07 0.67 Mag Stearate 2257 10.50 6.56 Eudragit S100 24.1815.11 Imwitor 900K 2.43 1.52 Dibutyl Sebacate 2.43 1.52 Tween 80 0.960.60 160.00 100.00

Example 6

A formulation was made with a pellet core as in Example 1, a sustainedrelease coating as in Example 2 and a pH dependent coating with a 50%weight gain as in Example 3.

TABLE 14 Component mg/1 g pellet % w/w Dextroamphetamine Sulfate USP22.00 12.22 Avicel PH-101 65.00 36.11 Starch 1500 10.00 5.56 Methocel E5P LV¹ 3.00 1.67 Ethocel Std 10 14.75 8.19 Klucel EF 3.69 2.05 DibutylSebacate 1.07 0.59 Mag Stearate 2257 10.50 5.83 Eudragit S100 40.3022.39 Imwitor 900K 4.05 2.25 Dibutyl Sebacate 4.05 2.25 Tween 80 1.600.89 180.00 100.00

Example 7

An example of a sustained release coating with an alternate ratio ofwater-soluble (Klucel) to water-insoluble polymer (Ethocel) is preparedwith the following components to obtain a faster release profile.

Core batch size—1100.0 g

Coating weight gain—30%

Solids—12.0%

TABLE 15 Component mg/1 g pellet solvent ratio % w/w g/batch Ethocel Std10 12.48 41.59 137.2 Klucel EF 3.12 10.40 34.3 Dibutyl Sebacate 0.903.01 9.9 Mag Stearate 2257 13.50 45.00 148.5 330.0 Ethanol 95 2299.0 DIWater 5 121.0 100.00 2750.0 Theoretical amount of 1430 coated pellets(g)

Example 8

A formulation was made with a pellet core as in Example 1, a sustainedrelease coating as in Example 7 and a pH dependent coating with a 30%weight gain as in Example 3.

TABLE 16 Component mg/1 g pellet % w/w Dextroamphetamine Sulfate USP22.00 13.75 Avicel PH-101 65.00 40.63 Starch 1500 10.00 6.25 Methocel E5P LV¹ 3.00 1.88 Ethocel Std 10 12.48 7.80 Klucel EF 3.12 1.95 DibutylSebacate 0.90 0.56 Mag Stearate 2257 13.50 8.44 Eudragit S100 24.1815.11 Imwitor 900K 2.43 1.52 Dibutyl Sebacate 2.43 1.52 Tween 80 0.960.60 160.00 100.00

Example 9

A formulation was made with a pellet core as in Example 1, a sustainedrelease coating as in Example 7 and a pH dependent coating with a 50%weight gain as in Example 4.

TABLE 17 Component mg/1 g pellet % w/w Dextroamphetamine Sulfate USP22.00 12.22 Avicel PH-101 65.00 36.11 Starch 1500 10.00 5.56 Methocel E5P LV¹ 3.00 1.67 Ethocel Std 10 12.48 6.93 Klucel EF 3.12 1.73 DibutylSebacate 0.90 0.50 Mag Stearate 2257 13.50 7.50 Eudragit S100 40.3022.39 Imwitor 900K 4.05 2.25 Dibutyl Sebacate 4.05 2.25 Tween 80 1.600.89 180.00 100.00

Example 10

Another example of a sustained release coating according to thedisclosure is prepared with the following components.

Core batch size—1100.0 g

Coating weight gain—30%

Solids—12.0%

TABLE 18 Component mg/1 g pellet solvent ratio % w/w g/batch Ethocel Std10 13.22 44.08 145.5 Klucel EF 3.1 11.02 36.4 Dibutyl Sebacate 1.47 4.9016.2 Mag Stearate 2257 12.00 40.00 132.0 Solvents Ethanol 95 2299.0 DIWater 5 121.0 100.00 2750.0 Theoretical amount of coated pellets 1430(g)

Example 11

A formulation was made with a pellet core as in Example 1, a sustainedrelease coating as in Example 10 and a pH dependent coating with a 30%weight gain as in Example 3.

TABLE 19 Component mg/1 g pellet % w/w Dextroamphetamine Sulfate USP22.00 13.75 Avicel PH-101 65.00 40.63 Starch 1500 10.00 6.25 Methocel E5P LV¹ 3.00 1.88 Ethocel Std 10 13.22 8.27 Klucel EF 3.31 2.07 DibutylSebacate 1.47 0.92 Mag Stearate 2257 12.00 7.50 Eudragit S100 24.1815.11 Imwitor 900K 2.43 1.52 Dibutyl Sebacate 2.43 1.52 Tween 80 0.960.60 160.00 100.00

Example 12

An example of a core pellet free of starch or osmagent as describedherein contains the following components as produced in a 2 kg batch.These core pellets are used in Examples 17-21.

TABLE 20 Component mg/1 g pellet % w/w g/batch Dextroamphetamine 22022.0 440 Sulfate, USP Microcrystalline 780 78.0 1560 Cellulose, NF Total1000 100.0 2000 DI Water removed during processing 1440

Example 13

An example of a slow sustained release coating as described herein foruse in Slow Release Formulation (1 and 2) 25% SR+20% or 30% pH Coating.

TABLE 21 SR Coat Slow Release (1 and 2) Coating Weight gain: 25.0 Solids%: 12.0 solvent Component mg/g ratio % w/w g/batch Ethyl Cellulose, 81.58.15 123 NF Hydroxypropyl 20.4 2.04 31 Cellulose, NF Dibutyl Sebacate,5.9 0.59 9 NF Magnesium 58.0 5.80 88 Stearate, NF Ethanol 95 1742(denatured) DI Water 5 92 Theoretical amount of 1250 coated pellets (g)

Example 14

An example of a slow enteric coatings as described herein for use inSlow Release Formulation (1 and 2) 25% SR+20% or 30% pH Coating.

TABLE 22 S100 pH Dependent Coat Slow Release (1) Coating Weight gain:20% Solids %: 10% Batch size (g) 1500 Core pellet amount (g) 1250solvent Component mg/g ratio % w/w g/batch Methacrylic Acid CopolymerType-B 133.7 13.37 202 Mono-and Di-glycerides, NF 13.4 1.34 20 DibutylSebacate, NF 13.4 1.34 20 Polysorbate 80, NF 5.3 0.53 8 Ethanol(denatured) 94.4 2138 DI Water 5.6 113 Theoretical amount of coatedpellets (g) 1500

TABLE 23 S100 pH Dependent Coat Slow Release (2) Coating Weight gain:30% Solids %: 10% Batch size (g) 1625 Core pellet amount (g) 1250solvent Component mg/g ratio % w/w g/batch Methacrylic Acid 185.1 18.51302 Copolymer Type-B Mono-and Di- 18.6 1.86 30 Glycerides, NF DibutylSebacate, 18.6 1.86 30 NF Polysorbate 80, NF 7.4 0.74 12 Ethanol(denatured) 94.4 3206 DI Water 5.6 169 Theoretical amount of coatedpellets (g) 1625

Example 15

An example of a medium sustained release coating as described herein foruse in Medium Release Formulation (1 and 2) 20% SR+20% or 30% pHCoating.

TABLE 24 SR Coat Medium Release (1 and 2) Coating Weight gain: 20%Solids %: 12% solvent Component mg/g ratio % w/w g/batch EthylCellulose, NF 134.0 13.40 98 Hydroxypropyl 33.5 3.35 25 Cellulose, NFDibutyl Sebacate, NF 9.7 0.97 7 Magnesium Stearate, 95.5 9.55 70 NFEthanol (denatured) 95 1393 DI Water 5 73 Amount of coated pellets (g)1200

TABLE 25 S100 pH Dependent Coat Medium Release (1) Coating 20.0 Weightgain: Solids %: 10.0 Batch size (g) 1440 Core pellet amt 1000 (g)solvent Component mg/g ratio % w/w g/batch Methacrylic Acid 120.3 12.03193 Copolymer Type-B Mono-and Di- 13.6 1.36 19 Glycerides, NF DibutylSebacate, NF 13.6 1.36 19 Polysorbate 80, NF 5.4 0.54 8 Ethanol(denatured) 94.4 2077 DI Water 5.6 123 Amount of coated pellets (g) 1440

TABLE 26 S100 pH Dependent Coat Medium Release (2) Coating Weight 30%gain: Solids %: 10% Batch size (g) 1560 Core pellet amount 1200 (g)solvent Component mg/g ratio % w/w g/batch Methacrylic 185.1 18.51 290Acid Copolymer Type-B Mono-and Di- 18.6 1.86 29 Glycerides, NF Dibutyl18.6 1.86 29 Sebacate, NF Polysorbate 80, 7.3 0.73 12 NF Ethanol 94.43210 (denatured) DI Water 5.6 190 Amount of coated pellets (g) 1560

Example 16

An example of fast release coatings for Fast Release Formulation 20%SR+20% pH Coating.

TABLE 27 SR Coat Fast Release Coating Weight 20.0 gain: Solids %: 12solvent Component mg/g ratio % w/w g/batch Ethyl 57.5 5.75 83 Cellulose,NF Hydroxypropyl 14.4 1.44 21 Cellulose, NF Dibutyl 4.2 0.42 6 Sebacate,NF Magnesium 6.22 6.22 90 Stearate, NF Ethanol 95 1393 (denatured) DIWater 5 73 Amount of coated pellets (g) 1200

TABLE 28 S100 pH Dependent Coat Fast Release Coating Weight gain: 20%Solids %: 10% Batch size (g) 1440 Core pellet amount 1200 (g) solventComponent mg/g ratio % w/w g/batch Methacrylic Acid 133.7 13.37 193Copolymer Type- B Mono-and Di- 13.4 1.34 19 Glycerides, NF DibutylSebacate, 13.4 1.34 19 NF Polysorbate 80, 5.3 0.53 8 NF Ethanol 94.42077 (denatured) DI Water 5.6 123 Amount of coated pellets (g) 1440

Example 17

An example of a composition of Dextroamphetamine Sulfate, 30 mg capsules(Slow Release Formulation 1) with a core as described in Example 12, 25%sustained release coating weight gain, +20% delayed release (enteric)coating weight gain.

TABLE 29 Strength (label claim) Component and 30 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Dextroamphetamine Active 30.00 14.59 Sulfate, USP ingredientMicrocrystalline Cellulose, NF Binder 106.36 51.74 (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 16.76 8.15 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 4.19 2.04 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 1.21 0.59 Magnesium Stearate, NFHydrophobic 11.93 5.80 Component Film Methacrylic Acid Copolymer FilmFormer 27.48 13.37 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm Plasticizer 2.76 1.34 (Imwitor 900K) Dibutyl Sebacate, NF FilmPlasticizer 2.76 1.34 Polysorbate 80, NF Solubilizer 1.09 0.53 Talc USP,EP 1.02 0.50 Total 205.56 100.0

Example 18

An example of a composition of Dextroamphetamine Sulfate, 30 mg capsules(Slow Release Formulation 2) with a core as in Example 12, 25% sustainedrelease coating weight gain, +30% delayed release (enteric) coatingweight gain.

TABLE 30 Strength (label claim) Component and 30 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Dextroamphetamine Sulfate, Active 30.00 13.47 USP ingredientMicrocrystalline Cellulose, NF Binder 106.36 47.76 (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 16.76 7.53 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 4.19 1.88 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 1.21 0.54 Magnesium Stearate, NFHydrophobic 11.93 5.36 Component Film Methacrylic Acid Copolymer FilmFormer 41.22 18.51 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NF(Imwitor 900K) Film Plasticizer 4.14 1.86 Dibutyl Sebacate, NF FilmPlasticizer 4.14 1.86 Polysorbate 80, NF Solubilizer 1.64 0.74 Talc USP,EP 1.11 0.50 Total 222.7 100.0

Example 19

An example of a composition of Dextroamphetamine Sulfate, 30 mg capsules(Medium Release Formulation 1) with a core as in Example 12, 20%sustained release coating weight gain, +20% delayed release (enteric)coating weight gain.

TABLE 31 Strength (label claim) 30 mg Component and Quantity QualityStandard (and per unit Grade, if applicable) Function (mg) %Dextroamphetamine Sulfate, Active 30.00 15.44 USP ingredientMicrocrystalline Cellulose, Binder 106.36 54.73 NF (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 13.40 6.90 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 3.35 1.72 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 0.97 0.50 Magnesium Stearate, NFHydrophobic 9.55 4.91 Film Component Methacrylic Acid Copolymer FilmFormer 26.38 12.03 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm Plasticizer 2.65 1.36 (Imwitor 900K) Dibutyl Sebacate, NF FilmPlasticizer 2.65 1.36 Polysorbate 80, NF Solubilizer 1.05 0.54 Talc USP,EP 0.98 0.50 Total 194.34 100.0

Example 20

An example of a composition of Dextroamphetamine Sulfate, 30 mg capsules(Medium Release Formulation 2) with a core as in Example 12, 20%sustained release coating weight gain, +30% delayed release (enteric)coating weight gain.

TABLE 32 Strength (label claim) Component and 30 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Dextroamphetamine Sulfate, Active 30.00 14.03 USP ingredientMicrocrystalline Cellulose, NF Binder 106.36 49.75 (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 13.40 6.27 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 3.35 1.57 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 0.97 0.45 Magnesium Stearate, NFHydrophobic 9.55 4.47 Film Component Methacrylic Acid Copolymer FilmFormer 39.57 18.51 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm Plasticizer 3.98 1.86 (Imwitor 900K) Dibutyl Sebacate, NF FilmPlasticizer 3.98 1.86 Polysorbate 80, NF Solubilizer 1.57 0.73 Talc USP,EP 1.06 0.50 Total 213.79 100.0

Example 21

An example of a composition of Dextroamphetamine Sulfate, 30 mg capsules(Fast Release Formulation) with a core as in Example 12, 20% sustainedrelease coating weight gain, +20% delayed release (enteric) coatingweight gain.

TABLE 33 Strength (label claim) Component and 30 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Dextroamphetamine Sulfate, Active 30.00 15.20 USP ingredientMicrocrystalline Cellulose, NF Binder 106.36 53.90 (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 11.34 5.75 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 2.84 1.44 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 0.82 0.42 Magnesium Stearate, NFHydrophobic 12.27 6.22 Film Component Methacrylic Acid Copolymer FilmFormer 26.38 13.37 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm Plasticizer 2.65 1.34 (Imwitor 900K) Dibutyl Sebacate, NF FilmPlasticizer 2.65 1.34 Polysorbate 80, NF Solubilizer 1.05 0.53 Talc USP,EP 0.98 0.50 Total 197.34 100.0

Example 22

The five formulations described in Examples 17-21 were subjected todissolution testing as described. The dissolution data are shown in thefollowing table.

TABLE 34 FAST MEDIUM MEDIUM SLOW SLOW (446604) (446603) (446605)(446602) (446606) TIME 20% SR; 20% SR; 20% SR; 25% SR; 25% SR; (HOURS)20% EC 30% EC 20% EC 20% EC 30% EC 0. 0.0 0.0 0.0 0.0 0.0 2. 1.6 2.9 0.20.0 0.5 4. 2.4 5.7 0.6 0.0 1.3 6. 4.0 9.9 1.4 0.0 2.1 7. 6.6 13.1 2.51.1 2.7 8. 9.7 16.3 5.0 3.0 3.1 9. 15.0 19.6 11.9 7.9 3.3 10. 25.8 23.025.7 18.0 4.4 12. 57.7 39.1 60.6 47.6 14.4 14. 81.5 64.0 81.4 71.9 41.716. 91.7 79.7 90.5 85.1 66.4 20. 97.7 89.8 96.2 94.8 85.7

A graph of the dissolution data is shown in FIG. 16. As can be seen inthe graph, the formulations provided a delayed release of from 6-10hours followed by a sustained increasing release over the next 10 hours.

Example 23

A parallel, five-arm, open-label, single-dose, fasting study ofDextroamphetamine 30 mg capsules in healthy, non-smoking male subjectswas conducted, administering the five formulations described in Examples13-17 to 56 healthy male volunteers aged 18 to 45 years.

Five formulations were administered orally during the trial:

Treatment A: 1 Dextroamphetamine Sulfate Capsule, 30 mg, CII (20% SR,30% ER coat, Medium Release);

Treatment B: 1 Dextroamphetamine Sulfate Capsule, 30 mg, CII (25% SR,20% ER coat, Slow Release);

Treatment C: 1 Dextroamphetamine Sulfate Capsule, 30 mg, CII (20% SR,20% ER coat, Fast Release),

Treatment D: 1 Dextroamphetamine Sulfate Capsule, 30 mg, CII (25% SR,30% ER coat, Slow Release);

Treatment E: 1 Dextroamphetamine Sulfate Capsule, 30 mg, CII (20% SR,20% ER coat, Medium Release).

The pharmaceuticals were administered daily at 8 AM and plasmaamphetamine concentrations were determined hourly for 20 hours beginningat hour 2. Using the validated method (D24 Version 00),dextroamphetamine and the internal standard, amphetamine-d5, wereextracted from human plasma (200.0 μL), with potassiumethylenediaminetetraacetic acid (K2EDTA) as an anticoagulant, byliquid-liquid extraction, evaporation under nitrogen, and reconstitutionin 200.0 μL of mobile phase (0.05% Triflouroacetic Acid:Acetonitrile,80:20, v/v). An aliquot of this extract was injected into a HighPerformance Liquid Chromatography (HPLC) system, detected using an API3000 with HSID tandem mass spectrometer, and quantitated using peak arearatio method.

Method sensitivity and selectivity were achieved by detecting distinctprecursor to product ion mass transitions for dextroamphetamine(136.2→119.1) and the internal standard, amphetamine-d5 (141.2→124.1),at defined retention times under reverse chromatographic conditions.

Evaluation of the assay, using defined acceptance criteria, was carriedout by the construction of an eight (8) point calibration curve(excluding zero concentration) covering the range of 0.200 ng/mL to51.200 ng/mL for dextroamphetamine in human plasma. The slope andintercept of the calibration curves were determined through weightedlinear regression analysis (1/conc.²). Two calibration curves andduplicate QC samples (at three concentration levels) were analyzed alongwith each batch of the study samples. Peak area ratios were used todetermine the concentration of the standards, quality control samples,and the unknown study samples from the calibration curves.

The plasma concentrations are shown in FIG. 17, in which the beginningtime of day is set to 9 PM. An overlay of the pharmacokinetic data ofthree commercial formulations, Dexedrine, Adderall® XR and Vyvanse® areoverlayed with the data of FIG. 17 in FIG. 18.

As shown in the table below, at the early time points, 0-6 hours and0-10 hours, exposure was highest for Treatment A and this correlatedwith the early dissolution observed for this formulation. Exposure from0 to T_(max) was marginally higher for Treatment A than the othertreatments, but was more variable than Treatments B and C. Treatment Cwas higher than B but was more variable. For Treatment D the exposure 0to T_(max) was relatively high (considering total AUC_(0-inf)), but theTreatment D T_(max) values occurred later than the other treatments.

TABLE 35 Dextroamphetamine Partial Exposure Metrics AUC₀₋₆ AUC₀₋₁₀AUC_(0-Tmax) (ng · hr/mL) (ng · hr/mL) (ng · hr/mL) AUC_(0-inf (ng/mL))Treatment Mean (N) CV (%) Mean (N) CV (%) Mean CV (%) Mean CV(%) A 16.7(10)  29.9 63.8 (10) 23.9 286.0 60.2 991.5 42.6 B 2.1 (12) 78.8 32.9(12) 41.2 234.6 20.6 1142.4 16.7 C 6.5 (10) 38.1 30.7 (10) 40.5 278.537.4 1250.3 20.7 D 1.6 (12) 44.7  7.3 (12) 41.3 266.0 50.7 869.9 27.7 E2.1 (12) 33.3 27.3 (12) 34.0 264.2 60.2 1069.5 35.8

The mean T_(max) values for treatments A, B, C, D and E were 17.9, 16.4,17.7, 22.6 and 17.8 hours, respectively.

The early exposure (0-6 hours and 0-10 hours) provided by theseformulations was very low relative to AUC_(0-inf) and is shown in theTable below together with AUC_(0-Tmax) in terms of percentages of themean values of these partial exposure metrics relative to mean values ofAUC_(0-inf) for each of the five treatments

TABLE 36 Treatment AUC₀₋₆ AUC₀₋₁₀ AUC _(0-Tmax) A 1.7 6.4 28.8 B 0.1 2.920.5 C 0.5 2.5 22.3 D 0.2 0.8 30.6 E 0.2 2.6 24.7

The exposure was less than 2% for all treatments (0-6 hours) and lessthan 5% for the AUC (0-10 hours) except for Treatment A (6.4%).

Seventeen subjects experienced a total of 25 adverse events (“AEs”)during the study. The most frequent AEs are expressed as fractions,relative to the total number of AEs experienced after each treatment.

No AE was reported more than once after administration of Treatment A[Dextroamphetamine Sulfate Capsule, 30 mg, CII (20% SR, 30% pH coat,Medium Release)], Treatment C [Dextroamphetamine Sulfate Capsule, 30 mg,CII (20% SR, 20% pH coat, Fast Release)] and Treatment D[Dextroamphetamine Sulfate Capsule, 30 mg, CII (25% SR, 30% pH coat,Slow Release)].

After administration of Treatment B (Dextroamphetamine Sulfate Capsule,30 mg, CII (25% SR, 20% pH coat, Slow Release), the most frequently AEswere headache (2/7) and somnolence (2/7).

After administration of Treatment E [(Dextroamphetamine Sulfate Capsule,30 mg, CII (20% SR, 20% pH coat, Medium Release)], the most frequentlyAE was dry mouth (2/8).

No AE was reported after the end-of-study exam.

Five AEs were “probably” related to the study drug, and 12 AEs were“possibly” related to the study drug. All subjects who experienced AEsduring this study recovered completely.

No serious adverse events (SAEs) were reported.

Example 24

Composition of Methylphenidate, 54 mg Capsules (Slow ReleaseFormulation, 25% SR Weight Gain+30% pH Dependent Weight Gain)

TABLE 37 Strength (label claim) Component and 54 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Methylphenidate Hydrochloride, Active 54.00 13.54 USP, CII ingredientMicrocrystalline Cellulose, NF Binder 191.45 48.00 (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 30.16 7.56 Standard 10 Premium)Hydroxypropyl Cellulose, NF Film Former 7.54 1.89 (Klucel EF Pharm)Dibutyl Sebacate, NF Film Plasticizer 2.18 0.55 Magnesium Stearate, NFHydrophobic 21.48 5.39 Film Component Methacrylic Acid Copolymer FilmFormer 74.19 18.60 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm Plasticizer 7.46 1.87 (Imwitor 900K) Dibutyl Sebacate, NF FilmPlasticizer 7.46 1.87 Polysorbate 80, NF Solubilizer 2.95 0.74 Total398.87 100.0

Example 25

Composition of Methylphenidate, 54 mg Capsules (Slow ReleaseFormulation, 20% SR Weight Gain+20% pH Dependent Weight Gain)

TABLE 38 Strength (label claim) Component and 54 mg Quality StandardQuantity per (and Grade, if applicable) Function unit (mg) %Methylphenidate Active 54.00 15.28 Hydrochloride, USP, CII ingredientMicrocrystalline Cellulose, Binder 191.45 54.16 NF (Avicel PH-101) EthylCellulose, NF (Ethocel Film Former 20.42 5.78 Standard 10 Premium)Hydroxypropyl Cellulose, Film Former 5.11 1.45 NF (Klucel EF Pharm)Dibutyl Sebacate, NF Film 1.48 0.42 Plasticizer Magnesium Stearate, NFHydrophobic 22.09 6.25 Film Component Methacrylic Acid Copolymer FilmFormer 47.48 13.43 Type-B (Eudragit S 100) Mono-and Di-Glycerides, NFFilm 4.77 1.35 (Imwitor 900K) Plasticizer Dibutyl Sebacate, NF Film 4.771.35 Plasticizer Polysorbate 80, NF Solubilizer 1.89 0.53 Total 353.46100.0

Example 26

TABLE 39 Composition of Methylphenidate, 54 mg Capsules (Slow ReleaseFormulation, 20% SR Weight Gain + 30% EC pH Dependent Weight Gain)Strength (label claim) Component and Quality 54 mg Standard (and Grade,if Quantity per applicable) Function unit (mg) % Methylphenidate Active54.00 15.95 Hydrochloride, USP, CII ingredient MicrocrystallineCellulose, Binder 162.00 47.84 NF (Avicel PH-101) Ethyl Cellulose, NF(Ethocel Film Former 21.23 6.27 Standard 10 Premium) HydroxypropylCellulose, Film Former 5.31 1.57 NF (Klucel EF Pharm) Dibutyl Sebacate,NF Film 7.84 2.32 Plasticizer Magnesium Stearate, NF Hydrophobic 15.124.46 Film Component Methacrylic Acid Copolymer Film Former 62.68 18.51Type-B (Eudragit S 100) Mono-and Di-Glycerides, Film 6.30 1.86 NF(Imwitor 900K) Plasticizer Polysorbate 80, NF Solubilizer 2.49 0.74 TalcEncapsulation 1.68 0.50 Lubricant Total 338.65 100.0

TABLE 40 Composition of Methylphenidate, 54 mg Capsules (Fast ReleaseFormulation, 20% SR Weight Gain + 15% EC pH Dependent Weight Gain)Strength (label claim) Component and 54 mg Quality Standard (andQuantity per Grade, if applicable) Function unit (mg) % MethylphenidateActive 54.00 18.03 Hydrochloride, USP, CII ingredient MicrocrystallineCellulose, NF Binder 162.00 54.08 (Avicel PH-101) Ethyl Cellulose, NF(Ethocel Film Former 21.23 7.09 Standard 10 Premium) HydroxypropylCellulose, NF Film Former 5.31 1.77 (Klucel EF Pharm) Dibutyl Sebacate,NF Film 4.69 1.57 Plasticizer Magnesium Stearate, NF Hydrophobic 15.125.05 Film Component Methacrylic Acid Copolymer Film Former 31.34 10.46Type-B (Eudragit S 100) Mono-and Di-Glycerides, NF Film 3.15 1.05(Imwitor 900K) Plasticizer Polysorbate 80, NF Solubilizer 1.24 0.41 TalcEncapsulation 1.49 0.50 Lubricant Total 299.57 100.0

Example 27

Method of Processing Coated Methylphenidate Capsules

In a preferred manufacturing process, methylphenidate HCl andmicrocrystalline cellulose (Avicel PH-101) are blended in a HobartMixer. Purified water is added to the dry mixture and the wetgranulation is extruded (MG-55 Multi granulator). The extrudate is thenspheronized into pellets (Caleva Model # SPH250). The wet pellets aredried (Fluid Air Model #0050) and sieved (30 mesh <Acceptable <20 mesh).

The sustained release coating is added as follows: a dispersion of EthylCellulose NF (Ethocel Standard 10 Premium), Klucel EF, Dibutyl Sebacate,NF, magnesium stearate, NF, ethanol and purified water, USP is preparedin an overhead stirrer. The dispersion is applied to the uncoatedmethylphenidate pellets in the fluid bed and the coated pellets aresieved as before. It is understood that in this context of this example,the term “dispersion” can refer to various two phase systems in which atleast some solids are dispersed in a liquid phase. The term“dispersion”, as used herein, can thus include, but is in no waylimited, either wholly or partly, the concepts of colloids, emulsionsand/or suspensions.

The enteric coating is prepared as follows: a dispersion of MethacrylicAcid Copolymer Type B (Eudragit S 100), Mono and di-glycerides, NF(Inwitor 900K), Dibutyl Sebacate, NF, Polysorbate 80, NF, ethanol andpurified water, USP are mixed in an overhead stirrer to obtain adispersion. The dispersion is applied to the sustained release coatedmethylphenidate pellets in the fluid bed. The enteric coated pellets areencapsulated to obtain the methylphenidate capsules.

Example 28

This example describes results of a randomized, single-center,single-dose, open-label, crossover, comparative bioavailability study inhealthy adult volunteers. The study was designed to compare twomethylphenidate HCl modified release formulations with each other, andwith an immediate release, marketed formulation of methylphenidate HCl(Ritalin®).

This study compared 54 mg MPH00400 and 54 mg MPH00500, modified-releasemethylphenidate formulations, with 20 mg Ritalin®. A total of 12subjects were randomly assigned to 3 treatment sequence cohorts of 4subjects each, and received all 3 treatments in crossover fashion, withwashout periods between treatment doses of approximately 4 days. Theorder of treatment administrations for Cohort I was Ritalin®, MPH00400,MPH00500; for Cohort II was MPH00400, MPH00500, Ritalin®; and for CohortIII was MPH00500, Ritalin®, MPH00400.

MPH00400 consists of a slow-release capsule (20% sustained-releasecoating, 30% pH coat, slow release) of 54 mg methylphenidate as well asmicrocrystalline cellulose, ethyl cellulose, hydroxypropyl cellulose,dibutyl sebacate, magnesium stearate, methacrylic acid copolymer type-B(Eudragit S 100), mono- and diglycerides, dibutyl sebacate andpolysorbate 80 (total capsule weight: 338.65 mg). The formulation isdescribed in more detail in Table 39 in Example 26.

MPH00500 consists of a fast-release capsule (20% sustained-releasecoating, 15% pH coat, fast release) of 54 mg methylphenidate as well asmicrocrystalline cellulose, ethyl cellulose, hydroxypropyl cellulose,dibutyl sebacate, magnesium stearate, methacrylic acid copolymer type-B(Eudragit S 100), mono- and diglycerides, dibutyl sebacate andpolysorbate 80 (total capsule weight: 299.57 mg). The formulation isdescribed in more detail in Table 40 in Example 26.

MPH00400 and MPH00500 were administered orally with 240 mL roomtemperature water at approximately 9 PM, at least 3 hours afterconsuming a low-fat dietary supplement meal (350-450 kcal). For thepurpose of this study, subjects were considered to be in the fastedstate.

Blood samples for pharmacokinetic analysis were collected during thetreatment phase of the study. During treatment with Ritalin®, bloodsamples were collected 10 minutes predose and at 0.25, 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, 17, 20 and 24 hours postdose. Fortreatment with MPH00400 and MPH00500, blood samples were collected 10minutes predose and at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 24, 30, 36 and 48 hours postdose.

MPH00400 and MPH00500 are investigational modified-release formulationsof methylphenidate hydrochloride that have differing dissolution releaserates (slow and fast, respectively). The formulations consist of coateddrug particles (in the form of pellets) in a water-soluble capsuleshell. The pellets are coated with an outer delayed-release coating andan inner sustained-release coating over a drug-containing core, witheach unit capsule containing 54 mg methylphenidate. Two film-coated beadformulations have been developed for clinical study, the compositions ofwhich differ, to achieve a range of release profiles (slow release forMPH00400 and fast release for MPH00500).

Pharmacokinetic parameters for plasma methylphenidate were calculatedusing noncompartmental analyses, including:

-   -   AUC_(0-t): Area under the plasma concentration-time curve to        time point t (ng*h/mL), in which t is the last time point over        the time interval with a measurable drug concentration;    -   AUC_(0-∞): AUC to infinite time (ng*h/mL);    -   C_(max): Maximum drug concentration in plasma (ng/mL);    -   T_(max): Time to reach maximum concentration (h);    -   λz: Terminal elimination rate constant (hr-1);    -   t_(1/2): Half-life of elimination (h).

For bioequivalence testing, C_(max) values and AUC_(0-t) values weredose-normalized by dividing the individual value of the parameter by theweight of the drug administered (mg) for the treatments.

To explore the influence of subject weight on observed pharmacokineticexposure, the individual total exposure (AUC_(0-t)) and peak exposure(C_(max)) were normalized (corrected) for body weight. This process ofderiving the body weight corrected exposure (“DWN”) involved dividingthe value of individual parameters by the dose administered to thesubject in terms of mg/kg body weight.

Table 41 presents results of pharmacokinetic analyses for the PKevaluable analysis set. Reliable AUC_(0-∞) could not be obtained forMPH00400 or MPH00500 because of the formulations' late drug absorptions,which interfered with evaluation of the terminal elimination rateconstant. The AUC_(0-t) parameter (24 hours for Ritalin®, 48 hours forMPH00400 and MPH00500) was considered to be a reliable measure of totalexposure for all treatments. This parameter was used as the relativemeasure of total drug exposure for MPH00400 and MPH00500. A graph of thePK data is shown in FIG. 19.

Generally, the trend of mean concentration time values wasrepresentative of the individual subjects within a treatment. MPH00400was more slowly absorbed than MPH00500 (83.4 ng*h/mL vs. 82.6 ng*h/mL,respectively), but C_(max) for MPH00500 was higher than that forMPH00400 (7.48 ng/mL vs. 5.99 ng/mL, respectively), with a later T_(max)value for MPH00400 (15.58 h vs. 13.0 h for MPH00500).

The dose level of Ritalin® used in the study (20 mg) was selected withthe intention of matching an estimate of the expected peak C_(max) thatwould be provided by the 54-mg experimental formulations. The meanC_(max) value observed for Ritalin® treatment (8.9 ng/mL), however was19% higher than the observed mean value observed for MPH00500 (7.48ng/mL) and 49% higher than that observed for MPH00400 (5.99 ng/mL).

Mixed model analysis of methylphenidate parameters comparing MPH00400and MPH00500 with each other and to Ritalin® demonstrated that therelative dose-normalized bioavailability in terms of the mean ofindividual ratios for C_(max) of MPH00400 and MPH00500 to Ritalin® was25% and 30%, respectively. Based on the geometric mean ratios forAUC_(0-t), relative dose-normalized bioavailability compared withRitalin® was 73% and 72% for MPH00400 and MPH00500, respectively.

TABLE 41 Summary of Methylphenidate HCl Parameters, PharmacokineticEvaluable Analysis Set C_(max) T_(max) AUC_(0-t) Treatment (ng/ml) (h)(ng*hr/mL) MPH00400 Mean ± SD 5.99 ± 1.44 15.58 ± 1.73 83.4 ± 22.6 (n)Range 3.93,8.66 13.0,18.0 43.0,129.8 (min, max) Median 5.85 16.0 80.0 CV% 24.0 11.1 27.1 MPH00500 Mean ± SD 7.48 ± 2.96 13.0 ± 2.04 82.6 ± 23.1(n) Range 3.92,12.50 11.0,17.0 52.3,132.3 (min, max) Median 5.94 12.081.9 CV % 39.6 15.7 28.0 IR Mean ± SD 8.90 ± 2.40 1.54 ± 0.40 42.0 ±10.4 METHYL- (n) PHENIDATE Range 5.92,15.09 1.0,2.5 26.4,61.0 HCl (min,max) Median 8.55 1.50 40.0 CV % 27.0 25.7 24.8

Following evening administration of MPH00400 and MPH00500, there was adelay of approximately 6 hours prior to drug release the next morning.Exposure characteristics for both MPH00400 and MPH00500 were highlyextended throughout the day, but were even more extended for MPH00400,with a later mean T_(max) value for MPH00400 compared with that forMPH00500 (15.58 h vs. 13.0 h). The mean C_(max) value for Ritalin® was19% higher than for MPH00500 and 49% higher than that for MPH00400.

The PK data for the MPH00400, slow release formulation was also comparedto published PK data for a sustained release, marketed formulation ofmethylphenidate HCl, (Concerta®). The dosage strength of 80 mg MPH00400was chosen as the equivalent of 54 mg of Concerta®. The parameters forthe 80 mg dose are calculated from the 54 mg dose data based on a linearequivalence dosage model.

The comparison of the test formulation MPH00400 calculated to reflect an80 mg dose and the published Concerta® PK profile is shown in FIG. 20,again as mean plasma concentrations vs. time in hours. Eighty mg waschosen as the equivalent because the test formula is absorbed much lowerin the GI tract and may have decreased bioavailability. The comparisonsdemonstrate the pharmacokinetic equivalence of the reference and testformulations.

FIG. 21 shows the data as in FIG. 20 with the test subjects broken intotwo groups based on gender. The plasma levels are lower in the femalegroup, presumably due to the faster metabolism expected in femalesubjects.

TABLE 42 Comparison of test formulation MPH00400 calculated to reflectan 80 mg dose and the published Concerta ® PK profile C_(max) CV T_(max)CV AUC CV (ng/ml) (%) (hrs) (%) (ng · h/mL) (%) Concerta ® 10.5 32.4 7.220.8 118.9^(§) 38.6 (54 mg) MPH 00400 5.99 24.0 15.6 11.1 83.4^(§) 27.1*(54 mg) MPH 00400 8.87 24.0 15.6 11.1 123.6^(§) 27.1 (80 mg)***MPH00400 was the selected formulation for the HLD200 product forfurther development **Linear dose extrapolation from 54 mg doses ^(§)ForConcerta ® AUC_(0-inf) is shown from FDA Clin. Pharm. Review, for HLD200AUC_(0-τ) is shown where τ was 48 hours C_(max) Maximum plasma drugconcentration post dose T_(max) Time to maximum plasma concentration CVCoefficient of variation

Example 29

This example describes a Phase I, single center clinical trial examiningthe pharmacokinetic effects of 100 mg of HLD200 modified releaseformulations of methylphenidate in healthy adult volunteers in a fasted,fed and sprinkled state under a randomized three-way crossover design.The objective of the study is to determine the rate and extent ofabsorption (i.e., PK) of HLD200 modified release (MR) following singletreatment (B-HLD200) in healthy adult volunteers in fasted, fed, andsprinkled states as well as tolerability in healthy adult volunteers.

Single-treatment B-HLD200 (100 mg) administered p.o. in the lateevening, at approximately 9 PM with 240 ml of ambient temperature waterfollowing a fasted state, following a high fat meal, and when sprinkledin applesauce randomly crossed over to different treatment sequences in6 cohorts with 7 days of washout between treatment periods. PKparameters C_(max), T_(max) and AUC are shown in Table 41 for allsubjects and separated by gender.

A graph of the mean plasma concentration time values is shown in FIG.23. It can be seen that the PK curves exhibit lag and exposure profilessimilar to those in the reported adult clinical trials described above,which were conducted in a fasted state.

TABLE 43 Mean Methylphenidate Pharmacokinetic Parameters followingAdministration of 100 mg HLD200 to Adult Normal Volunteers in the Fed,Sprinkled on Food and Fasted States Treatment A Treatment B Treatment CPK (Fed) (Sprinkled) (Fasted) Parameter 100 mg 100 mg 100 mg Lagtime(hr) ± CV(%) All 5.30 ± 51.6  0.56 ± 240.5  4.5 ± 41.9 Subjects [N] [17][18] [18] Female ♀[N] 4.86 ± 52.5 0.00  4.0 ± 28.9 [7] [7] [7] Male ♂5.60 ± 52.6  0.91 ± 180.1 4.82 ± 46.2 [10] [11] [11] C_(max) ± CV (%)All 10.65 ± 43.5 12.58 ± 33.8  12.5 ± 31.4 Subjects [N] [17] [18] [18]Female ♀[N] 13.15 ± 44.7 14.99 ± 32.4  15.41 ± 29.1  [7] [7] [7] Male♂[N] 8.69 ± 29.2 11.04 ± 28.5  10.64 ± 19.8  [10] [11] [11] MedianT_(max) (hr) 18.0 15.02 15.06 [18] [18] All Range 14-22   12-16.0 12-20Subjects [N] [17] [18] [18] Female ♀[N] 18.00 16.00 16.00 [7] [7] [7]18-22 14-18 13-18 [7] [11] [11] Male ♂[N] 19.00 14.5 14.0 [10] [7] [7]14-22 12-16 12-20 [10] [11] [11] AUC_(0-t) ± CV (%) (ng · hr/mL) All164.3 ± 41.3  169.7 ± 37.2   166.5 ± 27.7  Subjects [N] [17] [18] [18]Female ♀[N] 197.3 ± 41.7  208.1 ± 35.4   191.6 ± 29.7  [7] [7] [7] Male♂[N] 141.2 ± 33.6  145.2 ± 29.4  150.6 ± 20.6  [10] [11] [11]AUC_(0-inf) ± CV (%) (ng · hr/mL) All 169.2 ± 41.5  173.2 ± 36.6  169.2± 27.6  Subjects [N] [17] [18] [18] Female ♀[N] 202.5 ± 42.0  212.1 ±35.0  194.4 ± 29.0  [7] [7] [7] Male ♂[N] 145.8 ± 34.1  148.5 ± 28.5 153.1 ± 21.4  [10] [11] [11]

Example 30

A multiple-cohort, open-label, single-dose, fasting study ofmethylphenidate 54 mg capsules was conducted, administering a singleformulation to 18 adolescent (aged 13-17) and 11 pediatric (aged 6-12)subjects diagnosed with ADHD. Formulations were administered orallyduring the trial.

A graph of the plasma methylphenidate concentrations for adolescent andpediatric subjects are shown in FIG. 23, in which the beginning time ofday is set to 9 PM (t=0 hours). The data is presented as dose-weightadjusted pharmacokinetic data for both adolescent and pediatricpopulations described above.

The mean values for the AUC₀₋₁₀, AUC_(0-Tmax), AUC_(0-t) and AUC_(0-inf)pharmacokinetic parameters for the adolescent subjects are presentedbelow in Table 44. This comparison serves to highlight that significantdrug release does not occur between the 9 PM administration of the drugand 7 AM the next morning.

TABLE 44 Comparison of Mean Values for Methylphenidate Partial ExposureMetrics (Adolescents) AUC ₀₋₁₀ AUC_(0-Tmax) AUC_(0-t) AUC_(0-inf)Subject (ng · hr/mL) Mean 1.1 32.1 105.5 109.6 SD 0.73 10.0 31.6 33.8 CV% 65.6 31.3 30.0 30.8

The mean values for the AUC₀₋₁₀, AUC_(0-Tmax), AUC_(0-t) and AUC_(0-inf)in children are shown below in Table 45. These data again highlight thelack of significant release of drug for up to 10 hours followingadministration (9 PM-7 AM).

TABLE 45 Comparison of Mean Values for Methylphenidate Partial AUCExposure Metrics (Children) AUC ₀₋₁₀ AUC_(0-Tmax) AUC_(0-t) AUC_(0-inf)Subject (ng · hr/mL) Mean 2.7 61.3 205.5 210.1 SD 1.6 22.3 80.4 80.9 CV% 58.1 36.5 39.1 38.5

A summary of the primary pharmacokinetic parameters from theadolescents, children and adults (previous first-in-man study) is shownin the Table 46 below. The dose body weight normalization of the meanAUC_(0-t) and C_(max) parameters shows that the three groups exhibitedclose similarity, but the mean dose body weight normalized C_(max) forthe children was lower than the adolescents by 16% and lower than theadults by 18.5%. However, the corresponding values for the dose bodyweight normalized AUC_(0-t) were almost the same for the three groups.The T_(max) parameter appeared to be occurring later (18.2 v 16.2 hours)in the children compared with the adolescents, but there no wasstatistical difference between the two groups using the Mann Whitney nonparametric test. The adult T_(max) data set was different from thechildren (p=0.03) but not different from the adolescents.

TABLE 46 Comparison of Mean Methylphenidate Pharmacokinetic Parametersfrom Groups Adolescents Children Adults Parameter N = 18 N = 11 N = 12Mean C_(max) (ng/mL) ± CV 7.17 ± 23.7 11.64 ± 36.3  5.99 ± 24.0 (%)Median T_(max) (Range) 16.3 (13.9-22.1) 18.2 (12.4-22.0) 16.0 (13-18)Mean AUC_(0-t) ± ng · hr/mL 105.5 ± 30.0  205.5 ± 39.1  83.4 ± 27.1 [CV(%)] Mean AUC0-inf ± CV (%) 109.6 ± 30.8  210.1 ± 38.5  † DWN*parameters Mean C_(max) (ng/mL)/ 8.84 ± 34.5 7.44 ± 30.1 9.13 ± 35.2[mg/kg] ± CV (%) Mean AUC_(0-t) (ng/mL/) 129.4 ± 34.8  129.7 ± 27.3 126.5 ± 35.5  [mg/kg] ± CV (%) Mean AUC_(0-inf) (ng/mL/) 134.4 ± 35.7 132.7 ± 27.2  † [mg/kg] ± CV (%) *dose in mg divided by body weight † nodata available

Ten of 18 adolescent subjects treated with HLD200 experienced a total of10 adverse events (“AEs”) during the study. Six of 11 pediatric subjectsexperience a total of 7 AEs. Upper abdominal pain and upper respiratoryinfection were both reported by two adolescent subjects who were treatedwith HLD200, but no other AE was reported more than once in this patientpopulation. Both dizziness and pharyngitis were reported in 2 pediatricsubjects treated with HLD200, but no other AE was reported more thanonce in this patient population. No adolescent subject reporteddizziness and no pediatric subject reported abdominal pain as AEs.

There were 5 treatment emergent adverse events (TEAEs), all mild inseverity, in the adolescent population thought to be possibly orprobably drug-related, and included upper abdominal pain (2occurrences), headache, vomiting and flatulence (one occurrence each).There were no TEAEs in the pediatric population. There were no seriousadverse events (SAEs) in either population.

Example 31

Dissolution of the fast, medium and slow release methylphenidateformulations with varying coating thicknesses was tested underconditions that simulate oral administration. As described above theconditions include the USP Apparatus I (Baskets) with agitation andplacing the composition in 700 ml aqueous solution of 0.1N HCl pH 1.1,for up to 2 hours followed by 2-6 hours in sodium phosphate buffer at pH6.0; followed by 6-20 hours in sodium phosphate buffer, pH 7.2, addingNaOH to adjust pH to 7.2.

FIG. 25 is a graph of the dissolution results for 2 formulations, (i) afast release formulation with a 20% weight gain SR coating and a 15%weight gain EC coating, and (ii) a slow release formulation with a 20%weight gain SR coating and a 30% weight gain EC coating. As shown in thefigure, the two formulations demonstrated at least an 8 hour lag inwhich there was no significant drug release and the lag is followed by asustained release period of 10-12 hours.

Example 32

A Phase III Clinical Endpoint Evaluation Study was conducted examiningthe safety and efficacy of two formulations of evening-dosed, delayedand extended release methylphenidate in pediatric subjects withAttention-Deficit Hyperactivity Disorder. The intent was to assess thedrug's safety, efficacy profile for control of ADHD symptoms during themorning routine and throughout the day in a target population. Fortyeight patients between the ages of 6-12 years old with ADHD wereenrolled and 43 (23 males, 20 females) were dosed, randomized andcompleted all study procedures

The CEES consisted of a 6-week treatment-optimization period whichallowed suitable time to titrate over the entire dosing range (20 mg, 40mg, 60 mg, 80 mg and 100 mg), and adjust dose time (9:00 PM+2 hrs) ifrequired, followed by a one week, double-blind, placebo-controlled,parallel-group assessment.

The drug administered during the trial was MPH Hydrochloride Capsules,54 mg, (20% SR, 30% pH coat, slow release), which is the IronshoreMPH00400 slow release formulation. MPH00400 consists of a slow-releasecapsule (20% sustained-release coating, 30% pH coat, slow release) ofmethylphenidate as well as microcrystalline cellulose, ethyl cellulose,hydroxypropyl cellulose, dibutyl sebacate, magnesium stearate,methacrylic acid copolymer type-B (Eudragit S 100), mono- anddiglycerides, dibutyl sebacate and polysorbate 80 (total capsule weight:338.65 mg). The formulation is described in more detail in Table 39 inExample 26. This formulation (B-HLD200) of 54 mg capsules was modifiedto produce 20 and 40 mg capsules for the purpose of the study.Individual subject's daily doses (20, 40, 60, 80 and 100 mg) areachieved utilizing units of 20 and/or 40 mg MPH capsules, as required,to achieve their daily treatment dose level.

The primary endpoint for the study was to demonstrate whether eveningtreatment with HLD-200 improves control of ADHD symptoms, compared toplacebo, from 8:00 am to 4:00 pm as measured by the Swanson, Kotkin,Agler, M-Flynn and Pelham (SKAMP) Rating Scale Combined Score (CS)administered during the Laboratory Classroom Test Day at the end of theTreatment/Test Phase. Secondary measures assessed during the LaboratoryClassroom Test Day were the SKAMP CS during the evening at 6 pm and 8pm, and the Permanent Product Measure of Performance (PERMP) CombinedScore (Math problems Attempted+Completed).

Secondary measures assessed prior to conducting the Laboratory Classroomfor the period during the last half of the 7-day, double blind,placebo-controlled treatment period were Conners' Global Index-Parent(CGI-P) Total Score, Clinical Global Impression (CGI) of Severity andImprovement (CGI-S and CGI-I) Score, ADHD Rating Scale on DSM-IVcriteria (ADHD-RS-IV) Total Score, and Parents Rating of Evening andMorning Behavior-Revised (PREMB-R). The Before School FunctionQuestionnaire (BSFQ) Total Score was used to evaluate control of ADHDsymptoms and improved function during the at-home morning routine.

The BSFQ scale was developed to assess commonly reported areas ofmorning dysfunction in children and adolescents with ADHD (Wilens, etal., 2010; 2013). There are two components of the BSFQ scale: a 20-itemquestionnaire completed by the clinician and/or the parent/guardian; anda 14-item self-report section completed by the subject in collaborationwith the parent/guardian. Both components are focused primarily on earlymorning, before school functioning from approximately 6 AM to 9 AM. The20-items BSFQ questionnaire, which is utilized in this study, has beenvalidated and shown to be reliable. It is rated on a Likert Scale from 0to 3; using the following rating methodology for symptom severity andfunctional impairment: 0=None; 1=Mild—somewhat different thanpeers/siblings, some days; 2=Moderate—different than peers/siblings,most days; and 3=Severe—different from peers all days, all settings. Inaddition, the rater is asked to record the following early morning timemanagement information: 1) Time to wake up and get out of bed: x (min)and 2) Time to complete routines (from out of bed to exit home): x(min). The 14-item self-report component has not yet demonstratedvalidity or reliability, and w is included as an endpoint in this study.As such, all references to the BSFQ in this protocol are specific to the20-item scale only.

Parents are instructed to complete the BSFQ on the final two school daymornings (i.e., between Monday and Friday) prior to their child's weeklystudy visit and to review the results with the Investigator at thatvisit. Based on this review, the Investigator then completes the BSFQscale for the combined two-day early morning period. Theseclinician-rated BSFQ assessments are completed at each of Visits 2, 3,4, 5, 6, 7, 8 and 9 and the total score is recorded in the CRF.

PERMP (Swanson, 1998) is a 10-minute written math test performed asseatwork in the laboratory school analog classroom. Subjects are givenfive pages of 80 math problems, and are instructed to work at theirdesks and to complete as many problems as possible in 10 minutes.Performance is measured by the number of math problems attempted(PERMP-A) and the number of math problems correctly completed (PERMP-C).Different levels of the math tests are used among the subjects to adjustfor ability as determined by the math pretest done at Visit 2 andpractice class session at Visit 8. In addition, different versions ofthe math tests for a given level are used across class sessions (orcycles), so that a subject does not take the same test more than onceduring a day. A stopwatch is used to time the test. Like SKAMP, PERMP iscollected during the final test Visit 9. In this study, both PERMP-A andPERMP-C are defined as secondary efficacy measures.

The SKAMP rating scale (Wigal and Wigal, 2006) is a 13-item independentobserver rating of subject impairment (7-point scale) of analogclassroom-observed behaviors during the laboratory school assessments.Items 1-4 represent an indication of subject attention (SKAMP-AS), items5-8 are an indication of deportment (SKAMP-DS), items 9-11 assessquality of work, and items 12-13 assess subject compliance with teacherand classroom rules. In this study, the total score of all SKAMP items(or SKAMP combined score) is defined as the primary efficacy parameter.

The SKAMP rating scale is collected during each of 8 class sessions atVisit 9, occurring at 8, 9, 10 AM, and 12, 2, 4, 6, 8 PM of thelaboratory school assessment day. The primary efficacy endpoint isdefined as the SKAMP combined scores obtained from 8 AM through 4 PMsessions in this study, and secondary endpoints include results oftesting at hours 6 and 8 PM to examine the extended time course of thetreatment effectiveness. Practice class sessions for the laboratoryschool assessment day are conducted at Visit 8.

Results of the SKAMP Analysis is shown in FIG. 26. The upper curvemarked with diamonds is the SKAMP combined score for the treated groupand the lower curve, marked with squares is the placebo group. As seenfrom the figure, the drug HLD-200 improved control of ADHD symptoms ascompared to placebo for at least an eight hour period, from 8:00 AM to4:00 PM after a single dose administered the evening before.

As shown in the data in FIG. 27, the evening dosing of HLD-200 alsocontrolled ADHD symptoms over a 12 hour period, from 8:00 AM to 8:00 PMwhen measured by the SKAMP combined score.

The trial also demonstrated that the treatment significantly improvedthe morning functioning of subjects over the trial based on the BSFQscores as compared to the base score, as shown in FIG. 28. Patients inthe HLD-200 treatment arm showed a 58.5% improvement in their BSFQscores at visit 9 (analog classroom test day) vs. their study initiation(visit 2) score.

The sustained improvement of ADHD symptoms over a 12 hour classroom testday after an evening dose is also demonstrated by the PERMP combinedscores as shown in FIG. 29. Again the upper curve marked by squares isthe treated arm and the lower curve, marked by diamonds is the placeboarm. These scores demonstrate statistically significant improvement overthe entire test day as compared to placebo, and further demonstrated aremarkable consistency of effect at every time point during the day.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and/or methods and in the steps or in the sequence of stepsof the methods described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents that are chemically or physiologicallyrelated may be substituted for the agents described herein while thesame or similar results would be achieved. All such similar substitutesand modifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

What is claimed is:
 1. A method of treating a pediatric or adolescent subject having Attention Deficit Hyperactivity Disorder (ADHD), comprising: orally administering a composition comprising coated particles, said particles comprising: a core comprising hydroxypropyl methylcellulose and microcrystalline cellulose, and an effective amount of methylphenidate hydrochloride; a sustained release layer enclosing the core, wherein the sustained release layer comprises dibutyl sebacate, ethyl cellulose, hydroxypropyl cellulose, and magnesium stearate; and a delayed release layer enclosing the sustained release layer, wherein the delayed release layer comprises dibutyl sebacate, methacrylic acid copolymer Type B, monoglycerides, diglycerides and polysorbate 80; wherein the composition provides at least a 6 hour lag time during which the composition releases no more than 5% of the total methylphenidate hydrochloride followed by a sustained release period with a median T_(max) of about 12-16 hours when administered to healthy adults.
 2. The method of claim 1, wherein the composition provides at least an 8 hour lag time during which the composition releases no more than about 5% of the total methylphenidate hydrochloride.
 3. The method of claim 1, wherein the composition provides at least a 10 hour lag time during which the composition releases no more than 10% of the total methylphenidate hydrochloride.
 4. The method of claim 1, wherein the composition is contained in a capsule comprising hydroxypropyl methylcellulose.
 5. The method of claim 1, wherein: the administering is in the evening; and the method provides the pediatric or adolescent subjects having Attention Deficit Hyperactivity Disorder (ADHD) with a significant improvement compared to a placebo in Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) combined scores for a period from about 11 hours through about 23 hours after the administering in the evening.
 6. The method of claim 1, wherein: the administering is in the evening; and the method provides pediatric or adolescent subjects having Attention Deficit Hyperactivity Disorder (ADHD) with a significant improvement compared to a placebo in ADHD Rating Scale (ADHD-RS-IV) Total Score, Before School Functioning Questionnaire (BSFQ) score, and/or Parent Rating of Evening and Morning Behavior-Revised (PREMB-R AM) score.
 7. The method of claim 1, wherein the effective amount is 20 mg, 40 mg, 60 mg, 80 mg or 100mg. 